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Review

pubs.acs.org/CR

1 Role of Marine Natural Products in the Genesis of Antiviral Agents †,# ‡ ,†,# 2 Vedanjali Gogineni, Raymond F. Schinazi, and Mark T. Hamann* † 3 Department of Pharmacognosy, Pharmacology, Chemistry & Biochemistry, University of Mississippi, School of Pharmacy, 4 University, Mississippi 38677, United States ‡ 5 Center for AIDS Research, Department of Pediatrics, Emory University/Veterans Affairs Medical Center, 1760 Haygood Drive NE, 67 Atlanta, Georgia 30322, United States

8 *S Supporting Information

18.4. Lectins X 51 18.5. Bioactive Peptides X 52 18.6. Miscellaneous Antivirals Possessing Anti- 53 HIV Activity X 54 19. Antivirals from Porifera Y 55 9 CONTENTS 19.1. Sesquiterpene Hydroquinones Y 56 19.2. Cyclic Depsipeptides Y 57 11 1. Introduction B 19.3. Alkaloids Z 58 12 2. Human Immunodeficiency Virus Demographics B 19.4. Diterpenes AC 59 13 2.1. Nomenclature of HIV/AIDS B 19.5. Sulfated Sterols AC 60 14 2.2. Emergence of Drugs From Marine Sources B 19.6. Miscellaneous Antivirals Possessing Anti- 61 15 2.3. History of AIDS/HIV C HIV Activity AC 62 16 2.4. Description of the Virus G 20. Marine Drugs for the Treatment of Other Viral 63 17 2.5. Virus Replication Cycle G Diseases AC 64 18 2.6. HIV−HCV Coinfection H 20.1. Hepatitis B AC 65 19 3. Pneumonia J 20.2. HCV AE 66 20 3.1. Past Pandemics K 20.3. HPV AE 67 21 3.2. Transmission and Pathogenesis K 20.4. Influenza Virus AE 68 22 3.3. Treatment K 20.5. Respiratory Syncytial Virus AG 69 23 4. Hepatitis B K 20.6. Dengue AG 70 24 4.1. Description of the Virus K 20.7. Herpes Simplex Virus (HSV) AG 71 25 4.2. HBV Viral Replication L 21. In the Pipeline: HIV and HCV Drugs under 72 26 4.3. Treatment L Development AH 73 27 5. Human Papilloma Virus M 21.1. HIV AH 74 28 6. Respiratory Syncytial Virus N 21.2. HCV AI 75 29 6.1. Treatment N 21.3. Pneumonia AI 76 30 7. Hepatitis E N 21.4. HBV AI 77 31 8. Dengue N 21.5. HPV AI 78 32 8.1. Pandemics of Dengue N 21.6. Norovirus AJ 79 33 8.2. Dengue Virus O 21.7. Influenza AJ 80 34 8.3. Transmission, Characteristics, and Treatment O 21.8. RSV AJ 81 35 9. Severe Acute Respiratory Syndrome O 21.9. Shingles AJ 82 36 10. Norovirus O 22. Conclusion AJ 83 37 10.1. Transmission and Treatment O Associated Content AK 84 38 11. Middle East Respiratory Syndrome Coronavirus P Supporting Information AK 85 39 12. West Nile P Author Information AK 86 40 13. and A P Corresponding Author AK 87 41 14. Rotavirus Q Present Address AK 88 42 15. Shingles Q Notes AK 89 43 16. Herpes Simplex Virus R Biographies AK 90 44 17. Ebola Virus S Acknowledgments AL 91 45 17.1. Description of EBOV S References AL 92 46 18. Marine Drugs for the Treatment of HIV/AIDS T 47 18.1. Phlorotannins V 48 18.2. Chitin, Chitosan, and Chitooligosaccharide 49 Derivatives V Received: November 2, 2013 50 18.3. Sulfated Polysaccharides W

© XXXX American Chemical Society A DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

1. INTRODUCTION HIV and the resulting AIDS-associated have 122 7 become an international epidemic, resulting in over 30 million 123 93 Mammals have complex biological systems and are constantly 8 AIDS-related deaths worldwide. In 2011, around 2.5 million 124 94 prone to infections by a wide array of bacteria, fungi, viruses, and people were diagnosed with HIV, and an estimated 1.7 million 125 men, women, and children died from the complications of AIDS. 126 Around 34 million people were living with HIV by the end of 127 2011, with 69% of those infected in Sub-Saharan Africa. 128 Following Sub-Saharan Africa, the regions most affected with 129 HIV are the Caribbean, Eastern Europe, and Central Asia, where 130 7 1% of infected adults were living in 2011. 131 In Asia, it is estimated that at least 4.8 million people are 132 currently living with HIV, with China accounting for 780 000 of 133 those infected individuals followed by Thailand and Indonesia. 134 Eastern Europe and Latin America each has around 1.4 million 135 9 infected people. 136 In the United States, more than half a million people have died 137 10 − from AIDS-related complications, and it has been estimated 138 3 5 7 Figure 1. Mortality versus viral diseases. that over 1.3 million people are infected with HIV, some of 139 11 whom may not even be aware of their status. Those at 140 greatest risk for infection include individuals engaged in high-risk 141 12 behaviors, such as intravenous drug use. During 2007, in the 142 United States, HIV was the fourth leading cause of death for 143 Latinos and Hispanics between the ages of 35−44 and the sixth 144 13 leading cause of death between the ages of 25−34. According 145 14 to the National HIV/AIDS strategy, HIV and AIDS are most 146 commonly seen among African Americans. AIDS was first 147 documented by the United States CDC in 1982, in two females, 148 one Latina and the other African American. The epidemic of 149 AIDS began to spread among the African American population 150 15 from this point forward. 151 2.1. Nomenclature of HIV/AIDS − 6 Figure 2. Incidence rates versus viral diseases.3 5 The first instances of AIDS can be traced back to 1981, when a 152 strange illness began occurring in the homosexual communities; 153 however, the pandemic is reported to have started in the late 154 95 parasites, a significant challenge to the constant development of 16 1 1970s originating in Africa. In 1982, AIDS had different names 155 96 disease-strains resistance to current drugs. As a result, there is that included gay cancer, gay-related immune deficiency 156 97 always a need to identify new anti-infective agents against these 17 18 (GRID), gay compromise syndrome, and community- 157 98 organisms. An anti-infective agent is defined by Webster as “an acquired immune dysfunction. The term AIDS derived its 158 99 agent capable of acting against an infection, by inhibiting the 19 acronym in July 1982, at a meeting in Washington, DC. Initially 159 100 spread of an infectious agent or by killing the infectious agent 2 it was thought to be the disease of the “four H club” that included 160 101 outright”. Some of the emerging and drug-resistant infectious 16 heroin addicts, hemophiliacs, homosexuals, and Haitians. 161 102 diseases having research priority are human immunodeficiency The virus that was known to cause AIDS was initially named as 162 103 virus (HIV) or AIDS, hepatitis B and C viruses, respiratory 16 lymphadenopathy-associated virus, or LAV, in May 1983. On 163 104 infections such as influenza and respiratory syncytial virus (RSV), 1 April 23, it was announced that the virus known to cause AIDS 164 f1f2 105 and dengue fever. Figures 1 and 2 provide us with the data in was isolated and was named Human T-cell Leukemia Virus-III 165 106 regards to the mortality and incidence rates, respectively, of 3−5 (HTLV-III). It was thought that the LAV and HTLV-III could be 166 107 people with viral diseases. 20 the same virus. In March 1985, the United States Food and 167 108 Search engines utilized to identify the literature reviewed here fi Drug Administration (FDA) licensed the first blood test for 168 109 include Google scholar, Sci nder, Pubmed, government docu- 21 AIDS created by Abbott Laboratories to identify possible 169 110 ments from the CDC, NIH, and the World Health Organization 22 antibodies (for HIV). The name HIV or Human Immunode- 170 111 (WHO), academic journals, and books. ficiency Virus was given by the International Commission on 171 16 2. HUMAN IMMUNODEFICIENCY VIRUS Virological Nomenclature in May 1986. 172 112 DEMOGRAPHICS 2.2. Emergence of Drugs From Marine Sources 113 HIV-1 and HIV-2 can infect humans and cause severe Nature plays an important role in the generation of unique drug 173 + 114 immunosuppression through depletion of CD4 cells. HIV-2 prototypes of which about 60% of anticancer agents are derived 174 115 was first isolated in West Africa in 1986, and its mode of from natural sources and around 95% of the earth’s biosphere are 175 23 116 transmission is similar to HIV-1 except that it is generally less represented by the marine ecosystem. Hence, marine sources 176 117 infectious and the disease develops more slowly and is milder. As can be an invaluable source for the discovery of new compounds 177 118 the disease progresses, there are more infections with shorter for the treatment of diseases like AIDS or cancer. As an example, 178 24 119 durations compared to that of HIV-1. HIV-2 is seen three compounds, spongosine, spongothymidine, and spon- 179 25 120 predominately in Africa, but increasing incidences have been gouridine, were isolated from Cryptotethia crypta, a Caribbean 180 6 121 documented in the United States since 1987. marine sponge. These compounds were some of the first 181

B DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Scheme 1. Systematic Representation of the Chronological Order of HIV-1 and HCV Drugs Having Similar Structures to Ara-C, the First Anticancer Lead from a Sponge; All the Drugs and Compounds Mentioned in This Scheme Are NRTIs except for (59), Which Is an HIV-1 , and (192), Which Is an HCV Nucleoside Inhibitor

182 reported as bioactive nucleosides isolated from a marine species. Since then, extensive investigations have taken place for the 197 183 The first anticancer lead from marine organisms was cytosine treatment of various diseases from marine sources as well as for 198 184 arabinoside or ara-C (1), a synthetic derivative developed from a the further development of nucleosides (Schemes 1 and 2). 199 s1s2 25 185 sponge natural product prototype. The syntheses of ara-C were 2.3. History of AIDS/HIV 186 first reported by Walwick in 1959, and Lee first reported the 26 Jerome Horwitz synthesized AZT (3) in 1964 as an anticancer 200 187 syntheses for ara-A (vidarabine) (2) in 1960. Ara-A was used as 16 drug. Samuel Broder and Hiroaki Mitsuya, who were 201 188 an antiviral agent for the treatment of herpes simplex virus type 1 investigators at the National Cancer Institute (NCI), determined 202 189 and type 2 infections for many years, although acyclovir (83)is its potent anti-HIV activity in February 1985, which led to its 203 190 more widely prescribed. Ara-C is used for the treatment of acute clinical development. In 1974, it was shown to inhibit the Friend 204 ’ 26 27 191 myelocytic leukaemia and Hodgkin s lymphoma. The above leukemia virus (murine leukemia virus) replication, and in 205 fi 192 mentioned drugs are the rst FDA-approved marine-derived 1986, the clinical trials were conducted on HIV-infected 206 16 193 products used for the treatment of disease. They were also the persons. The drug was first approved by the FDA in March 207 ′ 21 16 194 basis for the synthesis and development of (3 -azido- 1987 under the commercial name Retrovir. AZT (3) in its 208 195 3′-deoxythymidine, AZT or ZDV) (3), which was initially tested triphosphate form inhibits HIV reverse transcriptase, thereby 209 28 196 for cancer as an antibacterial but was later approved for HIV. blocking the expression of p24 gag protein of the virus. AZT 210

C DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Scheme 2. Systematic Representation of the Chronological Order of HIV-1 and HCV Drugs Having Similar Nuclei to Ara-A, an Antiviral Agent; All the Drugs and Compounds Mentioned in This Scheme Are NRTIs

21 211 (3) was the first drug to be used in the treatment of AIDS, and new non-nucleoside reverse transcriptase inhibitor (NNRTI) 238 212 the first AIDS campaign coordinated by the nation was launched viramune, also known as (9), was approved by the 239 29 40 213 in 1988. FDA, and in the same year, the viral load test called Amplicor 240 214 In October 1991, FDA approved or 2′,3′- HIV-1 Monitor Test was introduced. This test gave clinicians the 241 30 41 215 dideoxyinosine (4). In June 1992, , also known as ability to document the progression of the disease. In 242 216 2′,3′-dideoxycytidine (ddC) (5), a nucleoside reverse tran- September 1997, the FDA approved an NRTI combivir, which 243 8 39 217 scriptase inhibitor (NRTI), was approved by the FDA; it was is a combination of (8) and zidovudine (3). In 244 31 218 mainly used in patients who were resistant to AZT. During the 1998, two clinical trials proved that the combination of AZT (3) 245 219 same year, a combination therapy was developed that became with ddC (5) was much more effective in prolonging life and 246 32 42 220 successful in utilizing both AZT (3) and ddC (5). In 1993, delaying the disease compared to AZT (3) used alone. 247 33 43 221 many cases occurred where people were resistant to AZT (3), (10), another NRTI, was approved by the FDA in December of 248 8 222 and in June 1994 the FDA approved another NRTI, the same year. In 1999, the original source of HIV was found to 249 8,34 223 (6). It was also shown that the transmission of HIV from be from Pan troglodytes, a type of chimpanzee common in West 250 224 mother to child could be reduced by up to 66% with the use of Central Africa. It is hypothesized that the virus entered the 251 35 225 AZT (3) during pregnancy. A recent example corresponding to human population when hunters were exposed to the infected 252 44 226 this includes the antiretroviral therapy (ART) given 30 h after blood of the chimpanzee. 253 227 birth to an infant born with HIV-1 infection. ART was continued Nonoxynol-9, a spermicide, was proven to be an ineffective 254 45 228 with detection of HIV-1 DNA and RNA; after the discontinua- microbicide in the reduction of transmission of HIV during sex. 255 229 tion of the therapy when the child reached 18 months of age, the The first HIV vaccine trial took place in Oxford, U.K., in 256 46 230 child was found with undetectable HIV-1 antibodies, suggesting September of 2000. In 2001 an Indian company, Cipla, offered 257 47 231 that early ART may help alter the long-term persistence of HIV-1 AIDS drugs for as low as $1 per day, and in 2002 WHO 258 36 232 infection. However, the child was later found viral positive after provided guidelines for antiretroviral drugs and also released a list 259 48 233 two years off ART, suggesting continued challenges in of 12 drugs that could be used for AIDS. T-20 (Fuzeon) (15), a 260 37 49 234 controlling HIV infection. fusion inhibitor, also came into existence as an injectable drug, 261 235 In 1995 the protease inhibitor (invirase) (7) was bringing forth a new campaign for the control of the spread of 262 38 236 approved by the FDA, and during the same year in November, HIV that was called ABC, short for “Abstinence, Being faithful, 263 39 50 237 the FDA approved the NRTI lamivudine or 3TC (8). In 1996 a and Condom use”. 264

D DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 3. Anti-HIV-1 drugs referenced in the history. Compounds include saquinavir (7),412 nevirapine (9),412 (12), (13), (14),413 and fuzeon (15).414

8,56 265 A great mission of rescue was initiated by the former United approved (11), and on December 1, 2003, 281 266 States president George W. Bush in 2003 to combat AIDS in the World AIDS Day, the WHO declared a “three by five” campaign 282 51 267 Caribbean and in Africa. In the same year, Vaxgen made an of providing antiretroviral treatment to three million people in 283 57 268 announcement regarding the failure of the AIDS vaccine to resource-poor countries by 2005. Another similar policy called 284 52 269 reduce the HIV infection rate, and in November the vaccine the “Four Free and One Care” was declared by the Chinese 285 53 270 was found to be a failure in a clinical trial in Thailand. On government that included many services such as providing free 286 271 March 15, 2003, the FDA approved a new type of anti-HIV drug antiretroviral agents to the poor and rural communities, free 287 272 for the prevention of HIV entry into human cells. Fuzeon, also testing and counseling, free drugs for the prevention of the 288 273 known as or T-20 (15), was the first drug to be transmission from mother to child, free schools for orphans of 289 274 classified as a “fusion inhibitor”. Fuzeon was available in the form AIDS-related deaths, and proper care and economic help for 290 58 275 of an injection, and it could be used as combination therapy in people afflicted with HIV or AIDS. 291 54 276 patients resistant to other antiretroviral drugs. The unnatural L- In 2004, for the first time in their history, the Global Fund 292 59 277 nucleosides, lamivudine and emtricitabine, became commercially stopped the funding scheme to fight AIDS. In March, the first 293 278 available, and they revolutionized the treatment of HIV (and oral fluid rapid test for HIV was approved by the United States 294 60 279 hepatitis B virus (HBV)), since these drugs are now part of many FDA, and President George W. Bush’s PEPFAR, also known as 295 55 280 highly effective fixed-dose combinations. In July 2003, the FDA the “President’s Emergency Plan For AIDS Relief” was fully 296

E DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 4. Structure of HIV.

Figure 5. Schematic representation of the virus replication cycle.

297 implemented in June 2004. This was designed to focus on 15 In 2007, the FDA approved two new drugs, raltegravir 315 61 66 67 298 countries in Africa as well as Haiti, Guyana, and Vietnam. (Isentress) (12) and maraviroc (Selzentry) (13), that could 316 299 In January 2005, the FDA approved an antiretroviral agent co- be used in patients resistant to all other classes of anti-HIV drugs. 317 300 packaged drug regimen (lamivudine (8)/zidovudine (3) and In October the initial results of a vaccine being developed by 318 301 nevirapine (9)) made by Aspen Pharmacare, a South African Merck pharmaceutical company were found to be ineffective, 319 302 Company. This marked the first HIV drug regimen to be resulting in terminating the trial being conducted on hundreds of 320 68 303 approved by a non-United States based pharmaceutical participants. In 2008, the American funding program PEPFAR 321 304 company, a milestone that represented a huge turning point in was renewed for the treatment of HIV/AIDS, malaria, and 322 69 305 Africa for providing cheaper pharmaceutical treatments for HIV- tuberculosis for the years 2009−2013. 323 62 306 1. In September 2005, the patent period for AZT came to an In 2009 President Obama promised to lift the travel ban that 324 307 end, allowing many pharmaceutical companies to produce the had been implemented for 22 years that prevented people 325 62 70 308 drug and sell it at greatly reduced prices. In 2006, for the first infected with HIV/AIDS from entering the United States, and 326 71 309 time, a pill that could be taken only once a day for the treatment finally on January 2010 the ban was lifted. The results from a 327 310 of HIV-1 infection was approved in United States. Now widely microbicide trial CAPRISA 004 highlighted the biannual 328 311 used in first-line treatment, Atripla included a combination of International AIDS Conference in July 2010. According to 329 312 three drugs: Emtriva (emtricitabine (11)), Sustiva ( Phase IIb trial results, it was found to be safe and effective to use 330 313 (19)), and Viread ( fumarate or TDF- an antiretroviral-based gel on HIV-negative women that reduced 331 63−65 72 314 (16)). the risk of acquiring the infection by 40%. In October 2011, a 332

F DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

membrane by the virus when a new virus is formed from the cell. 352 Throughout the viral envelope, proteins including 72 copies of 353 complex HIV-1 protein called env are embedded. The surface of 354 the virus is spiked with these env copies and is called a “virion”. 355 env includes glycoprotein 120 (gp120), which is a cap containing 356 three molecules, and glycoprotein 41 (), which is a stem 357 with three molecules. These two proteins adhere to the structure 358 of the viral envelope, and research concerning an HIV vaccine is 359 76 mainly focused on these proteins. 360 A bullet-shaped capsid or core is present inside the viral 361 envelope that is made of ∼2000 copies of p24, the viral protein. 362 Surrounding the capsid are two single-stranded HIV-1 RNA, 363 each including a complete copy of the viral genes. Gag, pol, and 364 env are the three structural genes that carry information 365 necessary for the formation of structural proteins for new viral 366 particles. Similarly , nef, vif, vpr, vpu, and rev are the six 367 regulatory genes responsible for the control of the virus in 368 regards to infecting the host and producing the disease. An RNA 369 sequence called the long terminal repeat (LTR) is present at the 370 end of each strand of the viral RNA. These regions control the 371 production of the new viruses. The nucleocapsid protein p7 is 372 present in the core, and the matrix protein p17 is present 373 between the core and the envelope. The virus also requires three 374 415 416 enzymes for the completion of its replication cycle: reverse 375 Figure 6. Crystal structures of HIV reverse transcriptase, integrase, 76 RNA polymerase,417 and protease418 and scanning electron micrograph transcriptase, protease, and integrase (Figure 4). 376 f4 of HIV.419 Courtesy: National Institute of Allergy and Infectious 2.5. Virus Replication Cycle Diseases, http://www.nih.gov/science/hiv/. HIV can only reproduce in humans, and its replication cycle 377 occurs in six stages, beginning with its binding to a CD4 receptor 378 + 333 new drug application for a single-drug regimen also known as the along with one of the co-receptors (among the two) on the CD4 379 “ ” 334 QUAD pill was submitted by Gilead Sciences, Inc., and this T-lymphocyte surface. This leads to the fusion of the virus (HIV- 380 335 included (53), cobicistat (14), emtricitabine (11), 1) to the host cell, thereby leading to the release of viral RNA into 381 73 fi 336 and TDF (16). Truvada, a xed-dose combination of the cell. This is called the Binding and Fusion stage. In stage II, 382 337 emtricitabine and tenofovir disoproxil fumarate, was approved called the Reverse Transcription stage, the reverse transcriptase 383 338 by the FDA in July 2012 for the pre-exposure prophylaxis (PrEP) 74 enzyme present in the virus (HIV-1) converts single-stranded 384 339 of HIV and was manufactured by Gilead. or viral RNA to double-stranded viral DNA. Stage III is the 385 340 Tivicay was approved by the FDA in August 2013 and was Integration stage, where the viral DNA formed in stage II enters 386 341 marketed by ViiV Healthcare and manufactured by GSK for use 75 into the host cell nucleus and incorporates the viral DNA within 387 342 ̈ in treatment-naive and treatment-experienced patients. The the host cell’s own DNA by the viral enzyme integrase. This 388 343 history of HIV/AIDS is outlined from its conception until 2014, integrated viral DNA is called a provirus and could reproduce few 389 344 and all of the HIV/AIDS drugs that are currently available in the or no copies or remain inactive for many years. 390 345 market can only be used to prevent further replication of the virus The fourth stage, Transcription, is where the provirus 391 346 in the body and to extend the lifetime of people who are HIV- produces copies of the viral genome as well as messenger RNA 392 347 positive by a few more years. A cure to eradicate or eliminate HIV or mRNA (shorter strands of RNA) with the help of the host’s 393 f3 348 completely has yet to be identified (Figure 3). RNA polymerase enzymes. This occurs whenever a signal is sent 394 2.4. Description of the Virus to the host cell to become active. The mRNA produced above is 395 349 The virus particles are spherical with a diameter of one ten- used to further produce long chains of viral proteins. Assembly is 396 350 thousandth of a millimeter. The viral envelope, which is the outer the fifth stage, where the long chains are cut into shorter 397 351 coat, includes two layers of lipids that are taken from the human individual proteins by the viral enzyme protease. These proteins 398

Figure 7. NNRTIs used for the treatment of HIV that include (17),412 (18),412 efavirenz (19),412 and (20).412

G DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 8. Various NRRIs possessing anti-HCV activity. NRRIs include (21), 2′-C-methyladenosine (22), 7-deaza-7-fluoro-2′-C- methyladenosine (23), 2′-O-methylcytidine (24), 7-deaza-2′-C-methyladenosine (25), 2′-C-methylguanosine (26), 4′-azidocytidine (27), 2′-deoxy-2′- fluoro-2′-C-methylcytidine (28), and R1626 (29).

greatly increase for those that have additional risk factors such as 413 80 intravenous drug use. 414 HIV−HCV coinfection leads to higher concentrations of HCV 415 RNA, thereby increasing the risk of cirrhosis by accelerating the 416 progress of HCV-related liver disease. In HIV-infected persons, 417 the natural progression of HCV is drastically increased as a result 418 81 of the HCV infection simulating opportunistic diseases. 419 Transmission by sexual or vertical factors is more important in 420 cases of HIV than HCV, but coinfection of HIV−HCV increases 421 82 the risk of both vertical and sexual transmission of HCV. As the 422 infection of HIV progresses, it leads to a decrease in cell- 423 mediated immunity that further enhances HCV replication, 424 Figure 9. Structure−activity relationship (SAR) of anti-HCV NRRIs. leading to an increase in infection rate and hepatocyte injury. The 425 immune cells cannot respond to HCV in coinfected persons 426 83 399 along with the copies of viral RNA form a new virus particle. The because they are impaired. High CD4 cell counts can result in 427 fi 84 400 sixth and the nal stage is Budding. The above assembled virus significant fibrotic progression in coinfected patients. HIV− 428 401 buds out of the host cell. During this stage, the virus takes some of HCV coinfection also leads to hepatocellular carcinoma (HCC), 429 ’ 402 the cell s outer membrane that contains sugar or protein which is known to have a higher incidence compared to those 430 85 403 combinations called HIV glycoproteins. These are required by infected with HCV alone. 431 404 the virus in order to bind with the CD4 and the co-receptors. Along with liver problems, HIV−HCV coinfected people 432 405 After this is complete, these copies are now ready to infect new 77 exhibit symptoms of kidney disease and have a bleaker renal 433 f5f6 406 86,87 cells (Figures 5 and 6). prognosis. There is an increased risk of significant kidney 434 − 88 2.6. HIV HCV Coinfection function deterioration in HIV−HCV coinfected women. Other 435 407 HIV coinfection with virus (HCV) is common due to coinfected persons developed membranous nephropathy, 436 78 408 the shared routes of transmission, and it is known to affect immunotactoid glomerulopathy, mesangial proliferative glomer- 437 409 about one-third of all the people infected with HIV worldwide. ulonephritis, and immune-deposited collapsing glomerulop- 438 89 410 The prevalence can vary depending on the factors of trans- athy. In summary, these coinfections lead to complicated 439 79 411 mission. In the United States, approximately 25% of people diagnoses, clinical progression of the disease, monitoring, 440 78 412 infected with HIV are also infected with HCV. The statistics treatment, and the basic immunology. 441

H DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 10. Structures of (31),420 (32),421 (33),420 (34),422 (35),423 and (36).424

101 102,103 442 The treatment for the coinfection of HIV−HCV usually C-methylcytidine (28), oral prodrugs like R1626 (29), 472 443 includes dual combination therapy of (IFN)− and novel analogues of 4′-azido-2′-deoxynucleoside (Figure 473 f8 104 444 (RBV) and highly active antiretroviral therapy (HAART). 8). 474 f8 445 However, the coinfection increases the complexity of the To possess anti-HCV activity, the presence of a methyl group 475 446 treatment. Problems arise with the safety and efficacy of the or a fluorine group at the 2′-C position or an azido group at the 476 90 447 drugs in these individuals. There are viral genome replication 4′-C position is essential. Any new nucleoside derivatives 477 448 inhibitors that are used for the treatment of HIV−HCV containing both substitutions in a single molecule would be an 478 92 449 coinfection. area of exploration for anti-HCV activity (Figure 9). 479 f9 450 The clinical symptoms and pathogenesis of HIV and HCV are or GS-7977 (30), previously named as PSI- 480 105 451 similar. The polymerases of HIV include RNA-dependent DNA 7977, is a uridine nucleotide analogue currently in Phase 2 481 106 452 polymerase, also known as reverse transcriptase, and that of HCV trial for the treatment of HCV infection. It is a selective 482 453 includes RNA-dependent RNA polymerase, referred to as RNA inhibitor of HCV NS5B polymerase. Combination with 483 454 replicase. Whereas HIV protease is an aspartyl protease, HCV’s pegylated interferon and ribavirin is also being tried for the 484 107 455 protease is a serine protease. Some of the drugs belonging to efficacy of sofosbuvir (30)intreatingHCV, although 485 456 different categories used in the treatment of HIV and HCV are interferon-free treatments are now more popular (e.g., the use 486 457 mentioned below. of sofosbuvir (30) with the NS5A inhibitor ledipasvir (31), a 487 458 As of 2015, the only nucleotide reverse transcriptase inhibitor combination called Harvoni that has been approved by the FDA 488 108 459 (NtRTI) approved for the treatment of HIV is TDF or Viread in October 2014). Simeprevir (32), a second-generation 489 460 (16), although all the currently approved nucleoside analogues macrocyclic compound, is a NS3/4A HCV protease inhibitor 490 91 461 require phosphorylation for inhibition of HIV polymerase. The that binds non-covalently to the HCV protease and was 491 109 462 non-nucleoside reverse transcriptase inhibitors (NNRTIs) used approved by the FDA in November 2013. Daclatasvir (33), 492 463 in the treatment of HIV include nevirapine (9), rilpivirine or a NS5A replication complex inhibitor manufactured by Bristol- 493 8 464 edurant (17), etravirine (18), efavirenz (19), and delavirdine Myers Squibb, was in Phase III clinical trials in combination with 494 92 110 f7 465 (20)(Figure 7). sofosbuvir for the treatment of HCV, and its use in 495 466 The known nucleoside RNA replicase inhibitors (NRRIs) combination with other antiviral drugs for the treatment of 496 111 467 possessing anti-HCV activity in vitro known to date include HCV was declined by the FDA in November 2014. The FDA 497 93 94,95 468 valopicitabine (21), 2′-C-methyladenosine (22), 7-deaza- approved Viekira Pak in December 2014, which is a combination 498 94,96 469 7-fluoro-2′-C-methyladenosine (23), 2′-O-methylcytidine of ombitasvir (34), paritaprevir (ABT-450) (35), and 499 94 97 470 (24), 7-deaza-2′-C-methyladenosine (25), 2′-C-methylgua- (46) tablets that are co-packed with dasabuvir (36) tablets for the 500 98,99 100 112 471 nosine (26), 4′-azidocytidine (27), 2′-deoxy-2′-fluoro-2′- treatment of chronic HCV infection (Figure 10). 501 f10

I DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 12. (A) HCV protease inhibitors that include (47), (48), (49), and SCH446211 (50). (B) HIV-1 entry 427 412 inhibitors BMS-663068 (51) and (52). (C) HIV-1 Figure 11. HIV protease inhibitors including (37), integrase inhibitors elvitegravir (53)428 and dolutegravir (54). (D) HIV- (38),412 (39),412 (40),412 nelfinavir 126 412 412 425 412 412 1 NNRTIs lersivirine (55) and dapivirine (56). (E) HIV-1 (41), (42), (43), (44), maturation inhibitor, (64). brecanavir (45),426 and ritonavir (46).412

502 The proteases of HIV and HCV are attractive drug targets. The drugs that act at various stages of the viral replication cycle is 525 503 viral protease inhibitors used for the treatment of HIV include shown (Figure 13). 526 f13 504 amprenavir (37), indinavir (38), lopinavir (39), fosamprenavir 8 505 (40), nelfinavir (41), darunavir (42), tipranavir (43), and 3. PNEUMONIA 92 506 atazanavir (44). Another protease inhibitor, brecanavir (45), Pneumonia is the second leading cause of death globally, with 527 507 could be used in combination with ritonavir (46) for the around 3.3 million cases annually in the United States. The 528 113,114 f11 508 treatment of HIV-1-infected persons (Figure 11). proper to completely treat the disease state do not 529 137 509 The HCV serine protease inhibitors include boceprevir exist. Pneumonia can occur in continuum to the acute 530 115 116 117 510 (47), telaprevir (48), ciluprevir (49), and SCH446211 influenza syndrome when it is caused by the virus alone, termed 531 118 f12 511 (50)(Figure 12A). as “primary infection”, or it could be caused as a mixed infection 532 138 512 Other anti-HIV-1 drugs that are still in clinical trials include of viruses and bacteria that is termed as “secondary infection”, 533 119 120 513 entry inhibitors such as PRO 140, TNX-355 or , which often is difficult to identify the etiological pathogen with 534 121 122 514 BMS-663068 (51) and cenicriviroc (52), integrase many different bacterial strains such as Streptococcus pneumonia, 535 123 124 515 inhibitors such as elvitegravir (53) and dolutegravir (54), Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus 536 125 126 516 maturation inhibitor vivecon, NNRTIs like lersivirine (55) influenzae, and Legionella pneumophila. The common cause of 537 127 128 517 and dapivirine (56), and NRTIs like KP 1461 (57), death due to pneumonia is mainly from the secondary bacterial 538 129 130 131 518 (58), (59), (60), infections due to one or several of the above mentioned strains 539 132 133 519 festinavir (61), (62), and (63) leading to a combined bacterial/viral or post-influenza pneumo- 540 134 137 520 (Figure 12B, C, and D and Schemes 1 and 2). nia. 541 135 521 Bevirimat (64), a maturation inhibitor, and dexelvucitabine Influenza viruses belong to the family of Orthomyxoviridae and 542 136 522 or reverset (65), a NRTI, are examples of discontinued anti- are enveloped with lipids, negative sense, single-stranded, 543 523 HIV-1 drugs that have undergone clinical trials (Figure 12E and segmented RNA viruses that exist in three forms: influenza A, 544 524 Scheme 1). A schematic representation of all the anti-HIV-1 B, and C. Influenza A virus is known to infect mammals, 545

J DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 13. Schematic representation of all the anti-HIV-1 drugs that act at various stages of viral replication cycle including the crystal structures of CD4429 and CCR5.430

Figure 14. Neuraminidase inhibitors: (66) and (67); drugs: (68) and (69).

546 including horses and pigs, and birds, whereas influenza B and C replication. The newly formed viruses then infect the epithelial 568 139 547 are known to infect only humans. cells in large numbers and eliminate the synthesis of the critical 569 139 3.1. Past Pandemics proteins and lead to the death of the host cells. 570 3.3. Treatment 548 There are three known pandemics during the 20th century, fl 549 which include the 1918 H1N1, Spanish flu; the 1957 H2N2, Various antiviral drugs used for the treatment of in uenza 571 550 Asian flu; and the 1968 H3N2, Hong Kong flu. The Spanish flu include the neuraminidase inhibitors that include oseltamivir 572 140 551 pandemic resulted in higher morbidity and mortality compared (66) and zanamivir (67) and adamantane drugs that include 573 141 552 to the 1957 or 1968 pandemics that are thought to have their amantadine (68) and rimantadine (69). These antiviral drugs 574 553 origins in Asia. The 2009 A(H1N1) influenza virus was the first do not reduce the risk of complications, and vaccination is the 575 139 fl 142 554 influenza pandemic in the 21st century. only means of controlling or preventing in uenza (Figure 14). 576 f14 3.2. Transmission and Pathogenesis 4. HEPATITIS B 555 The cause of transmission could be through the spread of Hepatitis B is the third leading cause of death globally and also 577 556 droplets via small-sized aerosols produced from talking, the first major viral disease with which most people are 578 557 coughing, or sneezing. Patients exposed to mechanical 3 chronically infected. Currently, more than 240 million people 579 558 ventilation or intubations are infected through airborne trans- are carriers of hepatitis B and are at increased risk of developing 580 559 mission. The incubation period is about 24−48 h, and the viral hepatic decompensation, hepatocellular carcinoma, and cir- 581 560 shedding begins in 24 h in the absence of antiviral environ- fl 138 rhosis. Hepatitis B is a chronic necro-in ammatory liver disease 582 561 ment. caused by hepatitis B virus (HBV) that could be further divided 583 562 Following inhalation, the virus deposits on the epithelium of 143 into HBeAg positive and negative chronic hepatitis B. 584 563 the respiratory tract and becomes attached to the ciliated 4.1. Description of the Virus 564 epithelial cells through the surface hemagglutinin. Some of the 565 viral particles will be eliminated by the secretion of the IgA HBV is the smallest known DNA virus (hepadnavirus) 585 566 antibodies or mucociliary clearance. The viral particles then possessing only 3200 bases in its genome. The genome consists 586 567 invade the respiratory epithelial cells and continue the viral of circular DNA that is partly double-stranded where one strand 587

K DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

The viral particle has four mRNA transcripts whose functions 605 are known. The longest transcript is 3.5 kb that templates both 606 for expression of polymerase and pre-core/core proteins and also 607 for genome replication, while the second longest transcript that is 608 2.4 kb codes for HBsAg, pre-S1, and pre-S2. The third transcript 609 is 2.1 kb that codes for HBsAg and pre-S2, while the smallest 610 144 transcript is 0.7 kb encoding the X protein. 611 The core gene possessing the pre-core region codes both the 612 core antigen, HBcAg, and the cleavage product, HBeAg, which is 613 an e antigen. Transcription of pre-core leads in cleavage by 614 targeting the HBcAg to the endoplasmic reticulum (ER) and 615 further secretion of HBeAg. HBcAg is the integral part of the 616 core-particle and is essential for viral package. The pre-S gene on 617 the surface codes the viral envelope and is essential for HBV 618 144 attachment to hepatocytes. 619 4.2. HBV Viral Replication

HBV viral replication is known to proceed in three stages where 620 in the first phase the DNA strands are synthesized with the 621 Figure 15. Structure of hepatitis B virus with crystal structure of HBV e completion of the minus strand prior to the synthesis of the other 622 431 antigen and cryo-electron microscopy (CryoEM) structure of HBV strand. During the second phase, the virus polymerase acts as a 623 432 core antigen. reverse transcriptase, and in the final phase, the minus strand is 624 primed at the 5′ end with a terminal protein while the plus strand 625 is primed by oligoribonucleotide resulting from the genomic viral 626 144 RNA. 627 HBV binds to the surface of the cell followed by penetration 628 into the cell. The viral core then transports into the nucleus 629 where the circular viral DNA is further converted to covalently 630 closed circular DNA, cccDNA, that acts as a template for the 631 synthesis of viral RNA. HBV does not undergo integration 632 during normal replication as seen with retroviruses. The minus 633 strand DNA synthesis is initiated at the 3′ DRI with polymerase 634 as primer while the plus strand DNA synthesis is initiated at the 635 3′ DR2 and continues until the passage of the 5′ end of the minus 636 strand. This leads to the production of an open circular DNA 637 similar to the matured HBV. The matured core particles will then 638 be packed into HBsAg/pre-S in the ER and exported out of the 639 cell. The nucleus maintains a stable pool of cccDNA for the 640 transport of freshly synthesized DNA back to the nucleus (Figure 641 f16 144 16). 642 f16 4.3. Treatment

Lamivudine (8) is used in the treatment of HBV by inhibiting the 643 viral DNA synthesis from becoming incorporated into the 644 growing DNA and resulting in premature termination of the 645 Figure 16. Viral replication of Hepatitis B virus. 146 chain. Adefovir dipivoxil (70), a nucleotide analogue of AMP, 646 is the prodrug of adefovir used in the treatment of HBV by 647 588 is termed “minus”, which is almost completely circular and inhibiting both the DNA polymerase and also reverse tran- 648 589 includes overlapping genes encoding the replicative proteins like scriptase activities by incorporating into the viral DNA and 649 147 590 polymerase, X, and structural proteins like surface, core, and pre- resulting in chain termination. Entecavir (71) acts by 650 591 S, while the other is termed “plus”, which is short and varied in inhibiting the HBV replication at three different stages: DNA 651 144 f15 592 length (Figure 15). polymerase priming, negative-strand DNA reverse transcription, 652 143 593 ENH I and ENH II are two enhancer elements where ENH I and positive-strand DNA synthesis. Entecavir is also being 653 594 functions competently in the hepatocytes only and is tissue- used in persons suffering from chronic hepatitis B with 654 148 149 595 specific while ENH II acts on the surface gene promoters decompensated liver disease. Telbivudine (72), aL-655 144 150 596 stimulating the transcriptional activity. HBV has a nucleocap- reverse transcriptase inhibitor, is another 656 597 sid that is a 27 nm sphere bearing a core antigen along with HBV drug with selective potent antiviral activity against hepatitis B 657 143 598 e antigen, the viral DNA, and the DNA polymerase. The virus (Figure 17). 658 f17 599 nucleocapsid is enveloped with a HBV surface antigen, HBsAg, Emtricitabine (11), a potent HIV inhibitor, is also used in the 659 600 which has the determinant a. In addition to the determinant a, treatment of HBV by inhibiting the viral replication. Tenofovir 660 601 the nucleocapsid also carries one of the two pairs of the subtypes DF (16), a nucleotide analogue also used in the treatment of 661 143 602 w and r or d and y. This results in four subtypes of HBsAg that HIV, is used in persons with hepatitis B, especially those who 662 151 603 include ayr, ayw, adr, and adw, which represent the phenotypic are resistant to the treatment of lamivudine (8). Clevudine 663 145 152 604 expression of the HBV genotypes. (73), a pyrimidine nucleoside, is also effective in inhibiting the 664

L DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 17. HBV drugs: adefovir dipivoxil (70), entecavir (71), telbivudine (72), clevudine (73), and thymosin (74).

Figure 18. Structure of RSV along with crystal structures of nucleoprotein,433 matrix protein,434 and fusion protein.435

665 viral replication, but it is only approved in South Korea. play the major role. Anogenital human papilloma virus (HPV) 673 153 154 666 Thymosin (74), a thymic-derived peptide, has the potency to infection is known to be transmitted through sexual contact. 674 HPVs are non-enveloped, double-stranded DNA viruses 675 667 stimulate the function of T-cells and is still under clinical trials 143 668 (Figure 17 and Schemes 1 and 2). belonging to the family Papillomaviridae. They are known to 676 infect the skin mucosal surfaces and epithelial cells. The virus has 677 5. HUMAN PAPILLOMA VIRUS a circular genome that is 8.0 kb and is encircled in a protein shell 678 made of major, L1 and minor, L2 capsid proteins. There are fi 679 669 Papillomaviruses were rst discovered as viral particles in 1949 seven ORFs (open reading frames) that encode the viral proteins 680 fi 670 with around 73 more genotypes identi ed later. Papillomaviruses with six “early” proteins, E1−E6. The early proteins are encoded 681 671 are found in mammals, birds, and reptiles like turtles. The mode by the transcripts present in the suprabasal and basal epithelial 682 672 of transmission is not clear, but the basal layer infections seem to cells that allow viral transcription and replication. The E6 and E7 683

M DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

684 proteins play a major role in the cell transformation and developing countries apart from Asia and is a major concern in 729 164 685 immortalization. The L1 ORF encrypts the viral protein shell and pregnant women, leading to liver disease. 730 686 its surface, while the L2 ORF encrypts the capsid mass, playing a HEV has been categorized in the genus Hepevirus belonging to 731 687 major role in the viral genome encapsulation. The L1 protein also the family Hepeviridae. Hepatitis E viral genome is 7.2 kb in size 732 155 688 helps in assembling the structures to virus-like particles, VLPs. with three ORFs and 3′ and 5′ cis elements that play a major role 733 689 HPV results in various cancers and genital warts, especially in HEV transcription and replication. ORF1 encodes for 734 156 690 cervical cancer, with more than 100 types of HPV; the first replicase, methyl transferase, protease, and helicase; ORF2 735 691 FDA-approved test for its identification was the cobas HPV test encodes for the protein capsid, and ORF3 encodes for a protein 736 157 164 692 in 2011, which is a follow-up to the Pap test. The treatment of of non-defined function. 737 693 HPV does not include specific antiviral therapy except for the The natural host for HEV is humans, with animals acting as a 738 164 694 presence of lesions, and two vaccines have been licensed in the possible reservoir in the amplification of the virus. The mode 739 695 United States against HPV 16 and 18 types causing cervical of transmission for HEV could be through transfusion. There is 740 156 696 cancer. no specific treatment for HEV infection, but ribavirin therapy has 741 been effective in some persons, although it is contraindicated 742 6. RESPIRATORY SYNCYTIAL VIRUS with pregnant women. Combination of ribavirin (75) and 743 α 697 Respiratory syncytial virus (RSV) is considered the major interferon- has also been used in chronically infected 744 158 163 698 pediatric respiratory pathogen, which was first isolated from a patients. Sofosbuvir was reported at the EASL (European 745 Association for the Study of the Liver) 2015 meeting to be a 746 165 modest inhibitor of HEV in culture. 747 8. DENGUE Dengue and dengue hemorrhagic fever, DHF, are arthropod- 748 166 borne viral infections known to be caused by the four virus 749

Figure 19. Chemical structure of ribavirin (75).

159 699 chimpanzee, causing life threatening illness during the first few 700 months. RSV has been placed in the genus Pneumovirus 158 701 belonging to the family Paramyxoviridae. 702 RSV is a medium-sized, linear, enveloped RNA virus with 10 703 viral polypeptides of which 8 are structural proteins with 7 largest 704 that include SH, L, F, P, M, N, and G and two NS proteins, NS1 705 and NS2. The polymerase (L), nucleoprotein (N), and 706 phosphoprotein (P) are the viral capsid proteins linked with 707 the mRNA genome. The non-glycosylated membrane proteins 708 M and M2 are the two matrix proteins. The attachment protein Figure 20. Structure of dengue virus along with the crystal structure of 436 709 (G), the small non-glycosylated hydrophobic protein (SH), and the envelope protein (E) 710 glycosylated fusion protein (F) are all part of the transmembrane 711 surface proteins. The G and F proteins play a major role in 158 f18 712 immunity (Figure 18). serotypes, DEN 1-4, belonging to the genus Flavivirus. People in 750 6.1. Treatment dengue endemic areas could have all four types of infections in 751 752 713 RSV is extremely contagious; at least half of the infants acquire their lifetime as cross-protective immunity is not provided when 753 714 RSV during their first year, and 40% of these result in lower infected with one of the serotypes. Dengue is considered an urban disease, and the virus completes its cycle in humans via the 754 715 respiratory tract diseases leading to pneumonia and/or 167 755 716 bronchiolitis. Ribavirin (75), a synthetic nucleoside, has been day-biting mosquito, Aedes aegypti. 717 approved for RSV infection, which is known to interfere with 8.1. Pandemics of Dengue 158 718 mRNA expression. Palivizumab (synagis), a humanized The first pandemic of dengue occurred in 1779−1780 in North 756 κ 160 719 monoclonal antibody, IgG1 , is another drug that was America, Asia, and Africa, where simultaneous outbreaks were 757 161 720 approved by the FDA in June 1998. Synagis is known to seen followed by a global pandemic after World War II in 758 160 721 possess fusion and neutralizing inhibitory activity against RSV. Southeast Asia. The geographical distribution of the multiple 759 fi 722 The rst vaccine for the treatment of RSV was developed in the viral serotypes expanded to the Americas, and the Pacific region 760 723 1960s, which was the alum-precipitated, formalin-inactivated and Southeast Asia had their epidemic in the 1950s, leading to 761 158 f19 724 vaccine (Figure 19). multiple hospitalizations and deaths by 1975 in many countries. 762 The Maldives, India, and Sri Lanka had their first epidemics in 763 7. HEPATITIS E the 1980s, whereas Pakistan had an epidemic in 1994. Although 764 725 Hepatitis E virus (HEV) is the causative organism of hepatitis E dengue was eradicated for a few years in the American region, it 765 162 167 726 and was initially termed as non-A, non-B hepatitis. HEV was slowly migrated into the United States by 1995. Dengue 766 727 recognized in the year 2004 as the major cause of acute hepatitis started to emerge worldwide, and currently an estimated 100 767 163 168 728 worldwide with four genotypes. HEV spread to other million people are at risk annually with this viral disease. 768

N DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

8.2. Dengue Virus

769 Dengue virus (DENV) belongs to the genus Flavivirus 770 comprising over 70 viruses, most of which are arthropod-borne 771 infections. The virus has a lipid envelope with an inner 772 nucleocapsid comprising single-stranded RNA and capsid 773 protein. The viral RNA is transformed into a polyprotein during 774 infection, which is further cleaved into structural and non- 775 structural (NS) proteins. The components of the matured viral 776 particles include the envelope (E), the structural capsid (C), and 777 the membrane (M), which are all thought to be involved in the f20 778 viral replication (Figure 20). 779 The NS proteins include NS1, NS2A−2B, NS3, NS4A−4B, 780 and NS5, which are only expressed in the host cell and thought to 781 play a role in viral replication. The function of NS1 is not 782 completely understood. NS2B, NS3, and its cofactor are known 783 to be involved in the process of the viral polyprotein, while NS3 Figure 21. Structure of the SARS virus along with the crystal structures 784 also shows nucleotide triphosphatase and RNA helicase of spike glycoprotein,437 nucleocapsid phosphoprotein,438 and RNA.439 785 activities. NS2A and NS4A−4B are hydrophobic proteins, and 786 their functions are not completely understood but are thought to The viral membrane includes the major proteins spike, S, and 826 787 be involved in anchoring viral replicase proteins to the cell membrane, M, which insert into the ER of the Golgi 827 788 membranes and contributing to the assembly of the virions; NS5 compartment while the RNA plus strands accumulate in the 828 789 plays a role in the capping of the viral RNA progenies. NS4A also nucleocapsid protein. The protein−RNA complex is then 829 790 has a role in membrane alterations and helps in the complex associated with the membrane protein of the ER, and the 830 169 791 formation of viral replicase. formed viral particles bud into the ER lumen. The viral particles 831 8.3. Transmission, Characteristics, and Treatment then migrate into the Golgi complex, exiting the cell by means of 832 171 exocytosis. 833 792 The primary vector of dengue is the Aedes mosquito, and There are no FDA-approved drugs for the treatment of SARS, 834 793 transmission to humans occurs from the bites of the infected although a few drugs like ribavirin have been considered but 835 794 − female mosquitoes. The incubation period is 4 10 days, and the proven to be ineffective in preventing SARS viral growth 836 795 infected mosquito has the ability to transmit the virus for the rest 172 ’ inhibition. The literature also shows the combination therapy 837 796 of the insect s life. The infected humans serve as the source of the with lopinavir (39)−ritonavir (46) for the treatment of SARS, 838 173 797 virus for the uninfected mosquitoes and could transmit the which is thought to reduce the viral load. 839 798 infection in 4−5 days during which the appearance of the first 799 symptoms occur. A secondary vector for the spread of dengue is 10. NOROVIRUS 168 800 Aedes albopictus. Noroviruses belonging to the family Caliciviridae (derived from 840 801 Dengue fever (DENF) is a severe, flu-like infection affecting 174 calyx, meaning “cup” in Greek) and the genus Norovirus were 841 802 adults, infants, and young children, leading to occasional deaths. discovered in the year 1972 and were previously called Norwalk- 842 803 The fever is usually accompanied by vomiting, rash, severe like viruses. Like other viruses, this virus also has a single-strand, 843 804 headache, joint and muscle pains, pain behind the eyes, and plus sense RNA of 7.5 kb including three ORFs. ORF1 is known 844 805 swollen glands. The symptoms last for about 2−7 days following to encode the non-structural polyprotein that could be cleaved by 845 806 the incubation period. Dengue becomes deadly when one or the viral protease into 6 proteins, while ORF2 and 3 encode the 846 807 more of the following symptoms occur: organ impairment, major and minor capsid proteins, VP1 and VP2, respectively. The 847 808 plasma leaking, respiratory stress, fluid accumulation, or severe 168 VP1 protein is involved in the formation of two domains: shell, S, 848 809 bleeding. Currently, there is no proper treatment or and protruding, P (P1 and P2). The P2 subdomain is further 849 810 175 vaccination for DENF. In cases of severe dengue, the medical involved in immune recognition and cellular interactions. The 850 811 practitioners and nurses give the necessary medical care and 168 virus-encoded 3C-like cysteine protease [3CLpro] processes the 851 812 ’ fl maintain the volumes of the patient s body uids. mature polyprotein for the generation of the six non-structural 852 proteins: p48 [NS1 and NS2], NTPase/RNA helicase [NS3], 853 9. SEVERE ACUTE RESPIRATORY SYNDROME p22 [NS4], VPg [NS5], protease [NS6], and a RNA-dependent 854 176 RNA polymerase [RdRp] [NS7]. 855 813 Severe acute respiratory syndrome (SARS) is caused by a 170 Five genotypes of noroviruses are known from the molecular 856 814 coronavirus and could be termed as atypical pneumonia, first characterization where GI, GII, and GIV are found in humans 857 815 identified in China in Guangdong Province, that later resulted in 171 while GIII and GV strains are seen in cattle and mice, 858 816 the spread to many countries. Coronaviruses belong to the 175 respectively. Noroviruses are the major causative organisms 859 817 family that includes enveloped viruses where the replication 177 of acute gastroenteritis. The common genotype responsible 860 818 occurs in the host-cell cytoplasm. They include a plus sense, 174 for many of the outbreaks worldwide is GII. 861 819 single-strand RNA with a 3′ polyadenylation tract and a 5′ cap 820 structure. Following the infection, the 5′ ORF of the virus is 10.1. Transmission and Treatment 821 transformed to a polyprotein that is further cleaved by the The primary mode of transmission includes either the oral or 862 822 proteases, releasing many nonstructural proteins that include the fecal routes, and the other common routes include water- or 863 823 ATPase helicase, Hel, and the RNA-dependent RNA polymer- foodborne and person-to-person contacts. Humans are thought 864 824 ase, which are responsible for the viral replication and protein to be the only hosts for human noroviruses. The virus can sustain 865 171 f21 825 synthesis (Figure 21). a wide range of temperatures and exists in various food items 866

O DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 22. Norovirus inhibitors: rupintrivir (76),440 (77), suramin (78),441 2′-C-methylcytidine (79), deubiquitinase [WP1130] (80), and elF4F inhibitors (81).

867 including fruits, vegetables, and raw oysters along with drinking currently includes Pipistrellus bat coronavirus HKU5 and 904 868 water. Noroviruses also result in repeated infections and undergo Tylonycteris bat coronavirus HKU4. This novel virus seem to 905 869 mutations, resulting in the evolution of novel strains infecting the relate to the viruses belonging to the families Nycteridae and 906 870 hosts. The disease results in fever, watery diarrhea, and vomiting Vespertilionidae that include insectivorous African and European 907 871 along with other symptoms such as myalgias, headaches, and bats, respectively. The infection is thought to be zoonotic 908 174 189 872 chills. primarily with limited transmission from human to human. 909 873 There are no known FDA-approved antiviral agents for the To date, there are no effective antivirals against MERS-CoV 910 874 treatment of norovirus gastroenteritis except for oral rehydration and emphasis is placed on organ support for renal and respiratory 911 875 with electrolytes and fluids. Antisecretory and antimotility drugs failures. IFN-α has shown inhibition of in vitro MERS-CoV 912 174 190 876 are used in adults suffering from diarrhea. Ribavirin (75) and replication while its action in vivo is unknown. 913 877 are known to inhibit the Norwalk viral replication 178 878 whose therapeutic efficacy needs further evaluation. Rupin- 12. WEST NILE 879 trivir (76), formerly known as AG7088, an irreversible inhibitor West Nile fever is a mosquito-borne viral disease that led to 914 880 of 3CLpro that possessed in vitro antiviral activity against 179 180 sporadic outbreaks of equine and human diseases in Europe. The 915 881 picornaviruses, is known to display anti-norovirus activity. largest outbreak occurred in 1996−1997 in Romania, near 916 882 Favipiravir (77), also known as T-705, currently in advanced Bucharest, which was considered the major arboviral illness in 917 883 clinical developments for influenza virus, is considered to be an 191 181 Europe. 918 884 RdRp inhibitor of norovirus, inhibiting the viral replication. West Nile virus (WNV), a member of the Japanese 919 885 Suramin (78), a naphthalene sulfonate derivative, is another encephalitis, belongs to the genus Flavivirus of the family 920 886 RdRp inhibitor that is known to inhibit the genome replication 182 Flaviviridae. This virus was initially isolated from the blood of a 921 887 ′ and prevent the synthesis of viral sub-genomic RNA. 2 -C- febrile female in Uganda in the year 1937 from the West Nile 922 888 Methylcytidine (79), a nucleoside analogue, is considered to be a district. The primary vectors of the virus include mosquitoes, 923 889 potent inhibitor of norovirus-induced diarrhea and mortality in 183,184 predominantly belonging to the genus Culex, and the primary 924 890 vitro in a mouse model. Certain deubiquitinase and elF4F 191 − hosts are wild birds. 925 891 inhibitors (80 81) are considered promising candidates in the Currently, there are no FDA-approved drugs or licensed 926 f22 892 development of norovirus therapeutics (Figures 19 and 192 185,186 vaccines available for the treatment of WNV. An adjuvant 927 f22 893 22). therapy used in the treatment of WNV encephalitis is 928 193 intravenous immunoglobulin (IVIG). 929 11. MIDDLE EAST RESPIRATORY SYNDROME 894 CORONAVIRUS 13. HEPATITIS D AND A 895 Middle Easy Respiratory Syndrome Coronavirus (MERS-CoV), Hepatitis D is caused by the hepatitis D virus (HDV) and leads to 930 896 a coronavirus that could lead to severe pulmonary disease in severe liver disease. Hepatitis D is uncommon in the United 931 187 897 humans, was first identified in Jeddah, Saudi Arabia, in States, and it generally occurs as a coinfection with hepatitis B 932 188 194 898 September 2012, from a patient suffering from renal failure virus. HDV is a hepatotropic defective virus that is dependent 933 899 and pneumonia. The infection is known to be linked geo- on the HBV for its envelope provision. HDV includes a hepatitis 934 900 graphically to the Middle Eastern countries like Saudi Arabia, the B surface antigen, HBsAg, and the RNA genome, which is a 935 189 901 United Arab Emirates, Jordan, and Qatar. rodlike, circular structure possessing self-ligation and autocata- 936 902 MERS-CoV belongs to the subfamily Coronavirinae that lytic cleavage properties. RNA polymerase II effects the RNA 937 903 represents a new species in the genus Betacoronavirus that replication, and the only protein that is encoded by the HDV− 938

P DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

939 RNA is the hepatitis D antigen, HDAg, whose short and long 15. SHINGLES 940 forms play a role in the morphogenesis and replication of the 195 Varicella-zoster virus (VZV) is a herpesvirus leading to both 979 941 virus. chicken pox (varicella) and shingles (herpes zoster). The virus 980 942 The only treatment available for chronic hepatitis D is alpha 943 interferon, although inhibiting HBV results in a decrease in 195 944 hepatitis D virus replication. Hepatitis D complications are 196 945 preventable with hepatitis B vaccine. 946 Hepatitis A is caused by the hepatitis A virus (HAV), an 197 947 enterovirus, belonging to the family Picornaviridae. The large 948 epidemics of hepatitis A occurred in the years 1954, 1961, and 198 949 1971. HAV has a single-molecule RNA surrounded by a small 950 protein capsid of 27 nm diameter and has an incubation period of 197 951 10−50 days. 952 Chronic infection is not seen with hepatitis A, and the 953 common mode of transmission is through person-to-person 954 contact with oral ingestion as the major route. The clinical illness 955 could be protected by giving immune globulin during the Figure 24. Structure of varicella-zoster virus (VZV). 956 incubation period or before the exposure to the HAV, and certain 198 957 hepatitis A vaccines are also effective against the disease. 14. ROTAVIRUS 958 Rotavirus is the leading cause of diarrhea among children 199 959 worldwide. The viral genome includes an 11-segmented

Figure 25. Chemical structures of valacyclovir (82), acyclovir (83), and famciclovir (84).

includes a nucleocapsid encapsulating the core with a linear 981 double-stranded DNA whose arrangement is done in short and 982 Figure 23. Structure of rotavirus along with the crystal structures of long unique segments with 69 ORFs with about 125 000 bp and a 983 442 443 444 VP7, VP1, and VP6. tegument made of protein that separates the capsid from the lipid 984 envelope. The lipid envelope incorporates the main viral 985 glycoproteins. VZV is the smallest known human herpesvirus 986 202 (Figure 24). 987 f24 960 double-stranded RNA that is enclosed in a three-layered viral People infected with chicken pox are prone to shingles that can 988 961 capsid with four major capsid proteinsVP2, VP4, VP6, and occur in all ages with the risk increasing with growing age. 989 962 VP7and two minor proteinsVP1 and VP3. The co- Chicken pox develops into blisters or rash, meaning that the virus 990 963 expression of the major capsid proteins as different combinations is dormant in the nerve cells and can reactivate by producing 991 203 964 resulted in the production of stable virus-like particles (VLPs) shingles and travel through the nerves to the skin. 992 965 that are responsible for the maintenance of the functional and Inflammation is seen in the nerves leading to after-pain, termed 993 966 structural characteristics of the matured viral particles. The outer as post-herpetic neuralgia (PHN) that could be chronic and 994 204 967 layer is composed of the glycoprotein, VP7, and dimeric spikes of severe. 995 968 VP4 responsible for inducing neutralizing antibodies, with VP4 VZV transmission occurs through respiratory route, and 996 969 as the viral hemagglutinin. The inner capsid has VP6 as the major zostavax is the vaccine used against VZV that has been approved 997 970 protein, which constitutes more than 80% that is known to by the FDA and is the only U.S.-licensed vaccine known to 998 204 971 possess RNA polymerase activity. The core part includes VP1− date. The antiviral drugs that have been approved for the 999 205 972 VP3, and the 11 double-stranded RNA segments with VP2 treatment of VZV infections include valacyclovir (82), 1000 200 206 207 f23 973 covering >90% of the core-protein mass (Figure 23). acyclovir (83), and famciclovir (84), which replaced the 1001 974 Rotavirus is known to infect the intestine, leading to diarrhea nucleoside analogues IFN-α and vidarabine or Ara-A (2). 1002 975 that could last for about 8 days. There is no treatment for Acyclovir (83) and valacyclovir (82) (a valine ester derivative of 1003 976 rotavirus infection, and this disease could be prevented through acyclovir) act as competitive inhibitors and result in the chain 1004 202 977 vaccination. The severity of the disease lies in dehydration that termination of the viral DNA polymerase. Varizig (varicella 1005 201 978 can be treated through fluids. zoster immune globulin) was approved by the U.S. FDA in 1006

Q DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

1007 December 2012 as an orphan drug that could be given after is highly common in the United States, and its transmission 1011 208 f25 1008 exposure to VZV (Figure 25 and Scheme 2). occurs through anal, oral, or vaginal sex with any person infected 1012 209 with the disease. 1013 16. HERPES SIMPLEX VIRUS Herpes simplex virus (HSV) is the largest herpes virus 1014 1009 Genital herpes, a sexually transmitted disease (STD), is caused belonging to the family Herpesviridae. The viruses belonging to 1015 1010 by two types of viruses, herpes simplex virus type 1 and type 2. It this family are enveloped viruses including a tegument, a capsid, 1016 and a genome. The viral envelope is fragile, and the space 1017 between the capsid and the viral envelope is called a tegument, 1018 which usually contains the glycoproteins and the enzymes 1019 necessary for the viral replication. The nucleocapsid is 1020 icosahedral with about 150 hexameric and 12 pentameric 1021 capsomeres that are doughnut-shaped. The viral genome is a 1022 210 linear, double-stranded DNA wrapped in a core (Figure 26). 1023 f26 HSV-1 and -2 have similar genome structures with 83% 1024 homology in the protein-coding and 40% homology in the 1025 sequencing regions. HSV-1 is associated with oral disease 1026 whereas HSV-2 is associated with genital disease in certain parts 1027 of the world such as Sub-Saharan Africa, where HSV-1 is known 1028 Figure 26. Structure of HSV. to occur in childhood and HSV-2 is sexually transmitted. In 1029 contrast, based on the anatomical site, HSV-2 is responsible for 1030 211 genital herpes in developed countries. 1031 Current medications for the treatment of HSV infection 1032 include antiviral agents like acyclovir (83), vidarabine (2), 1033 212 idoxuridine (85), ribavirin (75), and phosphonoformate 1034 213 (86), of which acyclovir or its valyl prodrug form known as 1035 valacyclovir is widely used. Acyclovir (83), a purine analogue, 1036 acts as a substrate for the viral thymidine kinase, thereby 1037 inhibiting the viral DNA polymerase selectively. Because of the 1038 viral resistance to acyclovir (83), new antivirals have evolved for 1039 Figure 27. Chemical structures of idoxuridine (85) and phosphono- the treatment of HSV. Phosphonoformate (86), which is a 1040 formate (86). derivative of phosphonoacetic acid, is a potent inhibitor of the 1041 f27

Figure 28. Structure of Ebola virus.220 Reprinted with permission from ref 210. Copyright 1989 American Chemical Society. Image from the RCSB PDB October 2014 Molecule of the Month featured by David Goodsell (DOI: 10.2210/rcsb_pdb/mom_2014_10)], crystal structures of glycoprotein,219 matrix proteins,445,446 and electron scanning microscopic image447 (Courtesy: National Institute of Allergy and Infectious Diseases, http://www.niaid. nih.gov/news/newsreleases/2014/Pages/EbolaDisparities.aspx).

R DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 29. Schematic representation of the marine metabolites that are active at various stages of the viral replication cycle including the crystal structure448 of lectin. f27 1042 HSV DNA polymerase (Scheme 2 and Figures 19, 25, and shares many features similar to the HIV envelope glycoprotein 1070 214 f27 1043 27). and influenza hemagglutinin covered with carbohydrate chains 1071 that would help the virus hide from the immune system. The 1072 17. EBOLA VIRUS virus could transform into a different shape when bound to the 1073 cell surface, dragging the cell and the virus close enough to cause 1074 1044 Ebola hemorrhagic fever (Ebola HF) is a viral disease caused by 220 membrane fusion. 1075 1045 the Ebola virus (EBOV) that gains importance in this review due The matrix protein, also called VP40, helps in the shape and 1076 1046 to the current, ongoing outbreak in West Africa along with 215 1047 Guinea, Liberia, and Uganda since March 2014. Reports budding of the virus. The proteins present on the membrane help 1077 1048 showed around 21 deaths and 37 cases that have been reported make the connection between the nucleocapsid and the 1078 1049 from Guinea, 13 cases from Sierra Leone, and 1 suspected case in membrane. The nucleocapsid, present at the center of the 1079 216 1050 Liberia between May 29 and June 1 of 2014. The number of virus, helps protect the viral genome; however, the nucleoprotein 1080 1051 ebola deaths has been raised since then to 7 857 between subunits are not rigid as in other viruses, showing a wavy 1081 220 1052 December 24 and 27 of 2014, with 3 413 deaths in Liberia, 2 732 structure. 1082 1053 deaths in Sierra Leone, 1 697 deaths in Guinea, 8 deaths in Transcription of the fourth gene leads to the expression of 1083 217 1054 Nigeria, 6 deaths in Mali, and 1 death in the United States. The glycoprotein that is transmembrane-linked (GP) and a secreted 1084 1055 first human outbreak of Ebola virus that has been recorded was in glycoprotein (sGP). GP remains the key target for the design of 1085 1056 1976 followed by major outbreaks in 2001 and 2003 in Gabon entry inhibitors and vaccines. GP is cleaved by furin post- 1086 218 1057 and the Republic of Congo. translationally yielding GP1 and GP2 subunits, which are 1087 17.1. Description of EBOV disulfide-linked. GP1 is known to effect the attachment to the 1088 host cells while GP2 facilitates the fusion of the host and viral 1089 1058 The EBOV is a non-segmented, enveloped, negative strand RNA 219 membranes (Figure 28). 1090 f28 1059 virus belonging to the family Filoviridae. Four species of EBOV There is no standard treatment for EBOV HF, but it is limited 1091 1060 (Sudan, Côte d’Ivoire, Reston, and Zaire) are known to cause to the supportive therapy that includes balancing the electrolytes 1092 1061 disease in humans, with Zaire being associated with the highest fl 1062 human lethality. The genome consists of seven genes responsible and uids of the patients, maintaining blood pressure and oxygen 1093 219 1063 for the synthesis of eight proteins. supply, and treating for further complicated infections. The early 1094 1064 Ebola virus is enclosed with a membrane of the infected cell symptoms of EBOV HF include fever and headache, which are 1095 ffi 1065 enveloped with ebola glycoproteins. The inner membrane is di cult to diagnose for EBOV. No known treatments are yet 1096 221 1066 supported with a layer of matrix proteins and possesses a central available for humans for the treatment of Ebola virus, but 1097 1067 cylindrical nucleocapsid that is necessary for the storage and recently favipiravir (77), a pyrazinecarboxamide derivative, 1098 1068 delivery of the RNA genome. The ebola glycoprotein binds to the showed successful suppression of the replication of Zaire 1099 μ 222 1069 cell-surface receptors to get the genome inside. The EBOV EBOV both in vitro and in vivo at an IC90 of 110 M. 1100

S DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 30. Phlorotannins 8,8′-bieckol (87), 8,4‴-dieckol (88), and 6,6′-bieckol (89) isolated from a brown algae, Ecklonia cava, and diphlorethohydroxycarmalol (90) isolated from Ishige okamurae.

18. MARINE DRUGS FOR THE TREATMENT OF 1101 HIV/AIDS

1102 Although there are many drugs available commercially from 1103 synthetic sources, limitations including drug resistance, side

Figure 32. Sulfated polysaccharides (94) isolated from red seaweeds.449

Figure 33. Structure of laminaran (95).

effects, cell toxicity, and long-term drug treatment are all possible 1104 explanations for the failure of the previously mentioned anti-HIV 1105 drugs. In addition, the evolution and development of nucleoside 1106 antivirals reveal the tremendous potential marine products have 1107 Figure 31. Sulfated chitin (91), chitosan (92), and chitooligosaccharide for the identification of novel prototypes and also reveals the 1108 (93) derivatives. necessity of developing drugs from natural resources such as the 1109

T DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 34. Structures of Leu-Leu-Glu-Tyr-Ser-Ile (96) and Leu-Leu-Glu-Tyr-Ser-Leu (97).

Figure 35. Structures of polyphemusin I (98)−II (99) and tachyplesins I (100)−II (101).

U DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 36. Structures of macrolactin-A (102), Da-1 (103), and AcDa-1 Figure 40. Structure of lamellarin α 20-sulfate (113). (104). linkage (fucophloroethols), and dibenzodioxin linkage (eck- 1123 227 ols). 8,4‴-Dieckol (88) and 8,8′-bieckol (87) are isolated 1124 from Ecklonia cava, a brown algae, and show inhibitory activity on 1125 HIV-1 reverse transcriptase and protease at inhibitory concen- 1126 μ 228 tration (IC50) values of 5.3 and 0.5 M, respectively. This is 1127 due to the inhibition of the gp41 six-helix bundle forma- 1128 229,230 tion. 6,6′-Bieckol (89), a natural derivate in Ecklonia cava, 1129 possesses lytic effects, causes p24 antigen production, and has 1130 inhibitory activity against HIV-1-induced syncytia formation. It 1131 Figure 37. Structures of equisetin (105) and phomasetin (106). showed selective inhibition against the HIV-1 entry and the 1132 activity of HIV-1 reverse transcriptase enzyme at an IC50 of 1.07 1133 231 μM. Diphlorethohydroxycarmalol (90), derived from Ishige 1134 okamurae, also possessed inhibitory activity against HIV-1. It 1135 inhibits HIV-1 reverse transcriptase and integrase at IC50 values 1136 232 of 9.1 and 25.2 μM, respectively (Figure 30). 1137 f30 ADMET predictor shows that 8,8′-bieckol (87), 8,4‴-dieckol 1138 (88), 6,6′-bieckol (89), and diphlorethohydroxycarmalol (90) 1139 violate three criteria of the Lipinski guidelines. These compounds 1140 also show low permeability and tend to be poor at permeating the 1141 cell membranes based on the polar surface area. 1142 6,6′-Bieckol (89), a phloroglucinol derivative, did not exhibit 1143 Figure 38. Structures of thalassiolins A (107), B (108), and C (109). any cytotoxicity at concentrations that inhibited HIV-1 1144 231 replication almost entirely. The phloroglucinol derivatives 1145 223 1110 marine environment. Marine species cover over two-thirds of exhibited HIV-1 inhibition similar to that of flavonoids where 1146 1111 the planet, making them a significant source for the production of they block the interaction between reverse transcriptase (RT) 1147 233 1112 novel compounds with possibly fewer adverse effects and higher and the RNA template. 6,6′-Bieckol (89) is a viral entry 1148 224 1113 inhibition activity. The compounds obtained from marine inhibitor, and so the above-mentioned factors like permeability 1149 1114 sources that are discussed in the following sections were found to may not be a problem; this could be considered as an important 1150 f29 1115 possess anti-HIV-1 activity (Figure 29). lead as this compound could inhibit the viral entry. 1151 18.1. Phlorotannins Most of the currently synthesized and FDA-approved drugs 1152 could only inhibit the virus at various replication stages. Hence, 1153 1116 Phlorotannins are tannin derivatives that were isolated from the above-mentioned limitations for various compounds could 1154 1117 brown algae and are biosynthesized by the polymerization of the be overcome by changing the route of administration (using 1155 1118 phloroglucinol monomer units acquired from the pathway of intravenous or subcutaneous instead of oral) (Table S1). 1156 1119 acetatemalonate. These are highly water-soluble com- 225,226 1120 pounds. They can be classified into four different 18.2. Chitin, Chitosan, and Chitooligosaccharide Derivatives 1121 categories: phlorotannins containing an ether linkage (fuhalols Chitin is widely found in crustaceans, fungi, invertebrates, and 1157 234 1122 and phlorethols), phenyl linkage (fucols), phenyl and ether insects. It is a long-chain polymer of N-acetylglucosamine that 1158

Figure 39. Structures of didemnaketals A (110) and B (111) and cyclodidemniserinol trisulfate (112).

V DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

235 1159 is most abundantly seen in the shells of shrimp and crabs. This polysaccharide suppressed the syncytial formation com- 1220 1160 Chitosan is formed by deacetylating chitin. The sulfated pletely at a concentration of 5 μg/mL and also inhibited the HIV- 1221 1161 derivatives of chitin (91) and chitosan (92) possess activities 1 reverse transcriptase at the same low concentration without any 1222 223 247 1162 including anti-HIV-1, antimicrobial, antioxidant, and others. cytotoxicity to the MT4 cells. Its mechanism of action involves 1223 1163 N-carboxymethylchitosan N,O-sulfate (NCMCS), a derivative of inhibiting the attachment of virus to the host cell. Nakashima et 1224 1164 N-carboxymethyl chitosan, is known to inhibit the transmission al. prepared an extract of citrate buffer, sea algal extract (SAE) 1225 + 1165 of HIV-1 in human CD4 cells. This inhibition is due to the from the marine red alga Schizymenia pacifica, that showed 1226 1166 blockade of the interactions between the glycoprotein receptors inhibition against HIV replication and HIV reverse transcriptase. 1227 1167 present on the viral coat and the target proteins present on the SAE is a sulfated polysaccharide with a molecular weight of 1228 1168 lymphocytes, thereby inhibiting the HIV-1 reverse tran- ∼2 000 000 belonging to the family of λ-carrageenan that 1229 236 1169 scriptase. The sulfation at the 2 and 3 positions led to the includes 3,6-anhydrogalactose (0.65%), sulfonate (20%), and 1230 1170 complete inhibition of HIV-1 infection to T-lymphocytes at 0.02 galactose (73%), with the sulfate residues being responsible for 1231 μ 1171 M concentrations without any cytotoxicity. These results show the inhibition of the HIV reverse transcriptase at an inhibitory 1232 3 248,249 1172 that the biological activity of the sulfated chitins can be controlled dose of 9.5 × 10 IU/mL. 1233 237 1173 by changing the sulfate group position. Chitosan is converted Brown algae are also known to produce SPs with anti-HIV-1 1234 223 1174 to chitooligosaccharides to improve its water solubility and, activity via a different mechanism of action. Fucans are present 1235 223 1175 therefore, its biological activity. mainly in brown algae, and they have high molecular weights and 1236 1176 Low molecular weight sulfated chitooligosaccharides possess a repeated chain of sulfated fucose. Fucans derived from 1237 238 1177 (SCOSs) (93) are known to possess anti-HIV activity. They the seaweed species of Lobophora variegate, Spatoglossum 1238 ff 250 1178 show lytic e ects and inhibit HIV-1-induced syncytia formation schroederi, Fucus vesiculosus, and Dictyota mertensii inhibit the 1239 ff 1179 at median e ective concentration (EC50) values of 1.43 and 2.19 reverse transcriptase of HIV-1. The galactofucan fractions of L. 1240 μ 1180 g/mL, respectively. The p24 antigen production could be variegate showed reverse transcriptase inhibition at 1.0 μg/mL 1241 μ 1181 suppressed at EC50 values of 7.76 and 4.33 g/mL for HIV-1Ba‑L 1242 238 concentration with 94% synthetic polynucleotides inhibition. 1182 and HIV-1RF, respectively. They also inhibited viral entry and Fucan A from D. mertensii and S. schroederi displayed inhibition 1243 1183 cell fusion by preventing the bond between gp120 of the HIV and 223 activity against the reverse transcriptase enzyme at 1.0 mg/mL 1244 f31 1184 CD4 surface receptor (Figure 31). with 99.3% and 99.03% inhibition, respectively. Fucan B from S. 1245 1185 ADMET predictor shows that sulfated chitins violate three schroederi showed inhibition activity of 53.9% at the same 1246 1186 criteria of the Lipinski guidelines whereas the chitosans violate all concentration. The fucan fraction from F. vesiculosus showed high 1247 1187 four criteria. In addition, they also show low permeability, low inhibition activity of 98.1% on the reverse transcriptase enzyme 1248 1188 flexibility, and a tendency to not permeate the cell membranes. 251 of HIV-1 at 0.5 μg/mL concentration. Similarly, fractions of 1249 1189 However, as per the mechanism of action, these are known to galactofucan from Adenocystis utricularis also presented anti-HIV- 1250 1190 inhibit the viral entry and fusion and so permeability could not be 1 activity by blocking the prior events of virus replication. EA1-20 1251 1191 considered as a limiting factor. and EC2-20 displayed strong inhibition activity on HIV-1 1252 1192 SCOSs inhibit HIV-1 replication by binding to the V3 loop of μ 238 replication at low IC50 values of 0.6 and 0.9 g/mL, 1253 1193 gp120 and thereby interfering with the gp120−CD4 binding. 252 respectively. SPs are also produced by the microalgae. 1254 1194 They possess a high rate of intestinal absorption, which is a 239 Naviculan is one such example that is isolated from Navicula 1255 1195 crucial property for a drug candidate. The main drawback with directa that possesses anti-HIV-1 activity. It demonstrated 1256 1196 chitosan and its sulfated oligosaccharide derivatives is its high inhibitory effect against the formation of cell−cell fusion between 1257 1197 anti-coagulant activity that limits SCOS to be clinically tested and 240 CD4-expressing HeLa cells and HIV gp160 at an IC50 value of 1258 1198 approved on infected HIV subjects. The above limitation 253 0.24 μM. A new type of D-galactan sulfate was isolated from 1259 1199 could be overcome by SAR (structure−activity relationship) Meretrix petechialis (clam) that possessed anti-HIV-1 activity by 1260 1200 studies and by trying various medicinal chemistry alterations to inhibiting syncytia formation at 200 μg/mL concentration with 1261 1201 alleviate the anticoagulant activity (Table S1). 254 56% inhibition. Laminaran (95), also termed laminarin, is a 1262 18.3. Sulfated Polysaccharides water-soluble polysaccharide including 20−25 glucose units 1263 β β 1202 Sulfated polysaccharides (94) are macromolecules that are possessing (1,3)- -D-glucan with (1,6) branching isolated from 1264 1203 chemically anionic and present in marine algae along with the brown algae. Laminaran (95) along with the laminaran 1265 1204 mammals and invertebrates, although marine algae are the major polysaccharides prepared from kelp are known to inhibit the HIV 1266 241,242 μ 1205 source. They also possess anti-HIV-1, along with reverse transcriptase and adsorption at a concentration of 50 g/ 1267 223 f32 1206 anticancer and anticoagulant activities (Figure 32). mL, suggesting good inhibition against HIV replication (Figure 1268 f33 255 1207 The SPs (sulfate polysaccharides) prevent the virus from 33). 1269 f33 1208 attaching to the target molecules on the cell surface. The SPs Galactan sulfate (GS), a polysaccharide isolated from 1270 1209 possess a binding site on the CD4 that is relatively similar to the Agardhiella tenera, a red seaweed, showed activity against HIV- 1271 243 μ 1210 HIV−gp120 binding region. Hence, by binding to this 1 and HIV-2 at IC50 values of 0.5 and 0.05 g/L, respectively. GS 1272 1211 lymphocyte, the SPs inhibit the binding of the monoclonal prevents the binding of HIV-1 to cells along with the binding of 1273 244 1212 antibodies to the initial two domains of the CD4, thereby anti-gp120 mAb to HIV-1 gp120. It is also known to be active 1274 1213 disrupting the CD4−gp120 interaction. The anti-HIV activity of against enveloped viruses including togaviruses, arenaviruses, 1275 256 1214 the SPs is by shielding off the positively charged sites on the V3 herpesviruses, and others. Carrageenans are extracted mainly 1276 1215 loop of the gp120 protein, thereby preventing the virus from certain genera of red seaweeds that include Hypnea, 1277 245 1216 attachment to the cell surface. Eucheuma, Gigartina, and Chondrus. Yamada and co-workers 1278 1217 The SPs from red algae are also known to possess anti-HIV-1 reported anti-HIV activity for O-acylated carrageenan poly- 1279 246 1218 activity. Schizymenia dubyi, a red algae, produces a sulfated saccharides with various molecular weights by means of sulfation 1280 257,258 1219 glucuronogalactan that is known to possess anti-HIV-1 activity. and depolymerization. 1281

W DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

1282 Calcium spirulan (Ca-SP), a sulfated polysaccharide isolated 18.5. Bioactive Peptides 1283 from the marine blue−green alga Arthrospira platensis, showed μ Bioactive peptides are widely isolated from marine organisms by 1342 1284 potent anti-HIV-1 activity at an IC50 value of 2900 g/mL and means of enzymatic hydrolysis. It is reported that many marine 1343 μ 223 1285 reduced viral replication at ED50 values of 11.4 and 2.3 g/mL. bioactive peptides have anti-HIV-1 activity. Some oysters 1344 1286 Ca-SP is also known to inhibit the viral replication of other possess antiviral and anti-bacterial substances that prevent 1345 1287 viruses that include HCMV, measles, polio, and coxsackie virus ff 1346 259 infectious diseases. Hence, a large isolation e ort has been 1288 by preventing the penetration of the virus into the host cells. made to discover HIV-1 protease inhibiting substances from the 1347 1289 Xin et al. reported 911, a marine polysaccharide derived from oyster Crassostrea gigas, yielding two peptides Leu-Leu-Glu-Tyr- 1348 1290 alginate that inhibited the HIV replication both in vivo and in Ser-Ile (96) and Leu-Leu-Glu-Tyr-Ser-Leu (97). They exhibited 1349 1291 vitro, attributing to the inhibition of the viral reverse tran- strong inhibition of the HIV-1 protease at IC50 values of 0.02 and 1350 1292 scriptase, interfering with the viral adsorption, and enhancing 0.015 μM, respectively. The inhibitory activity was found to be 1351 260,261 1293 immune function. Woo et al. reported the inhibitory effects related to the length of the amino acid sequence and the presence 1352 270 1294 of the marine shellfish polysaccharides from seven different of C-,N-terminal hydrophobic amino acid (Figure 34). 1353 f34 1295 shellfish, including Meretrix lusoria, Meretrix petechialis, Ruditapes Cyanovirin-N (CV-N) isolated from the cyanobacterium 1354 1296 philippinarum, Sinonovacula constricta Lamark, Scapharca sub- Nostoc ellipsosporum is a 101-amino-acid antiviral peptide with a 1355 1297 crenata, Scapharca broughtonii, and Mytilus coruscus, against HIV- molecular weight of 11 kDa with inhibitory effects against HIV-1 1356 1298 1 in vitro by inhibiting the viral fusion gp120/gp41 with the CD4 and HIV-2 at low nanomolar concentrations. CV-N prevents the 1357 262 1299 protein on the T-lymphocyte surface. transmission of HIV from infected to uninfected cells by 1358 245 271 1300 SPs effectively inhibit the cell−cell adhesion. Studies proved preventing cell-to-cell fusion. The peptides polyphemusins I 1359 1301 that SPs could be used as antiviral vaginal formulations because (98) and II (99) and tachyplesins I−III (100−101) isolated 1360 1302 they do not disturb the functions of the epithelial cells in the from the hemocyte debris of the horseshoe crabs Limulus 1361 223,245 1303 vagina or the normal bacterial flora. polyphemus and Tachypleus tridentatus were found to inhibit HIV 1362 272,273 18.4. Lectins cell fusion. Many synthetic peptide analogues have been 1363 prepared of which the synthetic peptide T22 analogue of 1364 1304 Lectins are proteins that bind to carbohydrates present in polyphemusin II (99) showed the strongest anti-HIV activity 1365 μ 1305 prokaryotes, algae, fungi, plants, corals, vertebrates, and with low in vitro cytotoxicity at EC50 value of 2.6 M, which is 1366 223 1306 invertebrates. They have specificity for different glycan comparatively less than that of azidothymidine (3) (5.2 μM) 1367 273 1307 structures. Hence, they bind to the glycans present on the (Figure 35). 1368 f35 1308 gp120 molecule of the HIV envelope, resulting in inhibition of 263 264,265 18.6. Miscellaneous Antivirals Possessing Anti-HIV Activity 1309 viralcellfusion, HIV infectivity, and syncytium 266 1310 formation. Several different lectins like griffithsin (GRFT), Macrolactin-A (102), an antiviral compound isolated from the 1369 1370 1311 obtained from the red algae Griffithsia sp., have been reported to marine bacteria, included 24-membered ring lactones, open- chain acids, and related glucose β-pyranosides that inhibited HIV 1371 1312 possess anti-HIV-1 activity. This lectin possesses about 120 274 replication at a concentration of 10 μg/mL. The diterpenes 1372 1313 common amino acids along with an unusual one at position 31. Da-1 (103) and AcDa-1 (104) isolated from Dictyota menstrualis, 1373 1314 The cytopathic effects produced by the laboratory strains and the the marine alga, inhibited the replication of HIV-1 virus at EC 1374 1315 HIV-1 clinical primary isolates on the T-lymphoblastic cells are 50 values of 40 and 70 μM, respectively. The above diterpenes did 1375 1316 inhibited at concentrations as low as 0.000043 μM. GRFT blocks not affect the viral internalization or viral attachment but instead 1376 1317 the cell-to-cell fusion of the uninfected and infected cells. It also inhibited the HIV reverse transcriptase at IC50 values of 10 and 1377 1318 prevents the binding of gp120, which is a CD4-dependent 275 267 35 μM, respectively (Figure 36). 1378 f36 1319 glycoprotein, with 2G12 and 48d monoclonal antibody. The antivirals equisetin (105) and phomasetin (106) isolated 1379 1320 In recent years, marine invertebrates have become new sources from the marine fungi Fusarium heterosporum and a Phoma sp. 1380 1321 for unusual lectins. One such example is CVL, a β-galactose showed inhibition against HIV-1 integrase at IC50 ranging 1381 1322 specific lectin isolated from Chaetopterus variopedatus, a marine 276 between 7 and 20 μM(Figure 37). 1382 f37 1323 worm. It inhibited the cytopathic effects caused by HIV-1 and the Thalassiolins A−C(107−109) isolated from the Caribbean 1383 1324 viral p24 antigen production at EC50 values of 0.0043 and 0.057 fl μ μ sea grass Thalassia testudinum are sulfated avone glycosides that 1384 1325 M, respectively. At an EC50 value of 0.073 M, CVL caused μ inhibited HIV replication at IC50 30 M, targeting the integrase- 1385 1326 blockade of HIV-1 infected and uninfected cell-to-cell fusion μ − μ catalyzed strand transfer at IC50 0.4 M. Thalassiolins A C 1386 1327 process. At concentrations of 0.07 and 0.33 M, CVL exhibited (107−109) showed potency against HIV integrase due to the 1387 277 1328 21% and 86% inhibition, respectively, of HIV-1 entry into the 1388 f38 268 presence of sulfated glucose functionality (Figure 38). 1329 host cells. Another lectin, CGL, isolated from the C. grayanus Didemnaketals A (110) and B (111), isolated from the 1389 ffi 1330 mussel, presented a high a nity to the mucin type glycoproteins. ascidian Didemnum sp., were shown to inhibit the HIV-protease 1390 278 1331 Two other lectins, DTL and DTL-A, were isolated from ascidium at IC values of 2 and 10 μM, respectively. Cyclo- 1391 269 50 1332 D. ternatanum. Similarly, SVL-1 and SVL-2, isolated from the didemniserinol trisulfate (112), isolated from the extracts of 1392 2+ 1333 marine worm Serpula vermicularis, are calcium (Ca )- Palauan ascidian Didemnum guttatum, showed inhibition of the 1393 223 1334 μ 279 independent lectins shown to possess anti-HIV-1 activity. HIV-integrase at IC50 60 g/mL (Figure 39). 1394 f39 1335 CGL, DTL, DTL-A, and SVL-2 displayed inhibition of HIV-1 Lamellarins were first isolated from the prosobranch mollusks 1395 280 1336 IIIB induced syncytium formation at EC50 values of 27.9, 0.002, belonging to the genus Lamellaria, and lamellarin α 20-sulfate 1396 1337 0.36, and 0.15 μg/mL, respectively. Among them, the CGL, (113), isolated from the Arabian Sea ascidian, was shown to 1397 1338 DTL, and DTL-A showed activity against the cell fusion between inhibit the HIV-integrase. Lamellarin α 20-sulfate (113) 1398 μ 1339 the HIV-1/H9 cells that are infected chronically and the inhibited the strand-transfer activity at an IC50 of 22 M and 1399 μ 1340 uninfected C8166 cells at EC50 values of 35.12, 1.37, and 6.97 the integrase terminal cleavage activity at IC50 of 16 M(Figure 1400 f40 269 281 1341 μg/mL, respectively. 40). 1401 f40

X DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

287 19. ANTIVIRALS FROM PORIFERA activity by inhibiting the reverse transcriptase enzyme or 1434 288 289 protease enzyme or by viral entry inhibition, whereas 1435 1402 Sponges have historically produced promising drug leads. Most 290 1436 1403 of the drugs obtained from sponges are being used for the indole alkaloids act as reverse transcriptase inhibitors. The anti-HIV-1 activity is known to increase with indole 1437 291 substitution. Hence, the analogues showed activity due to 1438 the presence of one of the above-mentioned moieties. The 1439 activity was shown to improve with the alkylation of the indole 1440 286 nitrogen as seen in analogue j (119)(Figure 42). 1441 f42 ADMET predictor shows that curcuphenol (116) and its 1442 analogues violate only one criterion of the Lipinski guidelines. 1443 Hence, they may be considered as potential candidates for the 1444 syntheses because as compared to some FDA-approved drugs 1445 Figure 41. Avarol (114) and avarone (115) possessing anti-HIV-1 like saquinavir (7) or fosamprenavir (40), which violate more 1446 activity. than one criterion, the limitations are less in this case (Table S1). 1447 282 19.2. Cyclic Depsipeptides 1404 treatment of HIV and also HSV. Some examples of the 1405 compounds isolated from sponges that are now being used for Papuamides, isolated from the marine sponges Theonella 1448 1406 the treatment of HIV-1 are discussed in detail in the following swinhoei and Theonella mirabilis, are known to possess anti- 1449 292 1407 sections. HIV-1 and cytotoxic effects. Papuamides A (121) and B (122) 1450 19.1. Sesquiterpene Hydroquinones were isolated from the sponge T. mirabilis and exhibited anti- 1451 μ 293 1408 Avarol (114) was first isolated from the marine sponge Disidea HIV-1 activity at a concentration of 0.003 M. Papuamides A 1452 1409 avara, and avarone (115) is synthesized by the silver oxide (121), B (122), C (123), and D (124) were isolated from T. 1453 283 282 1410 oxidation of avarol. These structures have a rearranged swinhoei (Figure 43). 1454 f43 284 1411 drimane skeleton. They showed an inhibitory effect on the Papuamide A (121) has a membrane-targeting mechanism, 1455 1412 replication of AIDS and HTLV IIIB-infected H9 human cells at and this mechanism of action has been shown to be responsible 1456 283 294 1413 0.3 μM. Its mechanism involves the blockade of p17 and p24 for its virucidal activity. Its mechanism of action involves 1457 1414 gag proteins after viral infection and, thereby, prevents inhibition of HIV pseudo-type viruses that express glycoprotein 1458 1415 replication of the virus. After further exploration of the envelope from the amphotropic murine leukemia virus or 1459 1416 mechanism of action, avarol was shown to block the tRNA, vesicular stomatitis virus, suggesting that the entry inhibition is 1460 fi 1417 required for glutamine synthesis, which plays a vital role in the not HIV-1 envelope glycoprotein speci c. It inhibits the virus 1461 f41 1418 synthesis of viral proteases necessary for its replication (Figure only at the initial stage of the viral replication cycle, and it targets 1462 282 f41 1419 41). the virus and not the cell. Hence, it exhibits a direct virucidal 1463 1420 ADMET predictor shows that avarol (114) violates only one mechanism of HIV-1. Papuamide B (122)targetsthe1464 1421 criterion of the Lipinski guidelines and avarone (115) does not phospholipid, phosphatidylserine (PS), present on the virus. 1465 1422 violate any. The carbonyl group of the quinone ring includes a Papuamides C (123) and D (124) also inhibit the viral entry 1466 294 1423 hydroxyl group at the ortho position, which is known to be (Figure 43). 1467 1424 responsiblefortheblockadeofthereversetranscriptase ADMET predictor shows that papuamides A (121), B (122), 1468 285 1425 activity. Hence, both of them may likely be good candidates C(123), and D (124) violate three criteria of the Lipinski 1469 1426 to be considered for further in vivo studies because the guidelines. They also show low flexibility and do not possess the 1470 1427 limitations are minor (Table S1). tendency to permeate the cell membranes. In addition, most 1471 1428 Curcuphenol (116), a sesquiterpene phenol, was isolated from peptide-derived drugs must be administered IV. This could 1472 1429 the sponges Didiscus oxeata, Didiscus flavus, Myrmekioderma styx, overcome the permeability limitation, and they also represent 1473 1430 and Epipolasis sp. Semi-synthetic analogues a (117), c (118), j potentially challenging molecules (Table S1). 1474 1431 (119), and r (120) had anti-HIV-1 activity at EC50 values of 31.2, Callipeltin A (125), isolated from a sponge belonging to the 1475 286 1432 29.2, 18.4, and 18.2 μM, respectively. Isoquinoline derivatives genus Callipelta, also possesses anti-HIV-1 activity. The HIV-1- 1476 1433 have been previously patented for the treatment of anti-HIV-1 induced cytopathic effects were inhibited at a median effective 1477

Figure 42. Curcuphenol (116) and its analogues a (117), c (118), j (119), and r (120) isolated and modified from the sponges Didiscus oxeata, Didiscus flavus, Myrmekioderma styx, and Epipolasis sp.

Y DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 43. Papuamides A (121), B (122), C (123), and D (124) isolated from the marine sponges Theonella swinhoei and T. mirabilis.

μ 295 1478 dose (ED50) value of 0.007 M. Similarly, neamphamide A 19.3. Alkaloids 1479 (126), isolated from Neamphius huxleyi, possesses cytoprotective 296 Dragmacidin F (131), a new bromoindole alkaloid isolated from 1523 1480 μ activity against HIV-1 infection at an EC50 value of 0.028 M. the sponge belonging to the genus Halicortex from the southern 1524 1481 Certain mirabamides that inhibit HIV-1 fusion were isolated coast of Ustica Island in Italy, showed in vitro activity against 1525 1482 from the sponge Siliquariaspongia mirabilis. Among them, μ HIV-1 and HSV-1 at EC50 values of 0.9 and 96 M, 1526 301 1483 mirabamide A (127) was shown to be active against HIV-1 respectively. This compound is known to inhibit the syncytia 1527 1484 fusion assays and neutralization at IC50 values between 0.04 and formation later to infecting the HIV-MT4, without causing any 1528 μ 301−303 1485 0.14 M, respectively. The mirabamides were shown to be more direct toxicity to the cell (Figure 46). 1529 f46 1486 selective for HIV-1 by inhibiting them at the membrane fusion 1530 297 ADMET predictor shows that dragmacidin F (131) violates 1487 level. Celebeside A (128) and theopapuamide B (129) were two criteria of the Lipinski guidelines. In addition, it also 1531 1488 also isolated from the same sponge, S. mirabilis. Celebeside A possesses a low tendency to permeate the cell membranes. 1532 1489 (128) showed HIV-1 entry inhibition at an IC50 value of 2.13 Because there is no direct toxicity involved to the cells using this 1533 μ 1490 M, whereas theopapuamide B (129) showed inhibition at an compound, the side effects could be reduced to some extent. 1534 μ 1491 IC50 value of 0.99 M. Additionally, celebeside A (128) possesses Fosamprenavir (40), an FDA-approved drug (Table S4), also 1535 1492 anti-HIV-1 activity due to the presence of a phosphoserine 1536 298 violates more than one criterion of the Lipinski guideline. Hence, f44 1493 residue that is absent in theopapuamide B (129)(Figure 44). this should not be a limiting factor for Dragmacidin F (131)to 1537 1494 ADMET predictor shows that callipeltin A (125), mirabamide avoid considering it for further development and bringing it to 1538 1495 A(127), and celebeside A (128) violate three criteria of Lipinski clinical trials (Table S1). 1539 304 1496 guidelines whereas neamphamide A (126) and theopapuamide B Manzamine A (132) was isolated from the Haliclona sp. It 1540 1497 (129) violate all four criteria. In addition, they also show low has a unique complex polycyclic ring system that is coupled with 1541 fl 1498 permeability, low exibility, and no tendency to permeate the cell a β-carboline moiety and is known to possess anti-HIV-1, 1542 282 1499 membranes. All of the above-mentioned compounds belong to antiparasitic, antimicrobial, and other biological activities. 1543 305 1500 the class of depsipeptides, and their mechanism of action is Manzamine A (132), 6-deoxymanzamine X (133), neokaulu- 1544 1501 similar to that of papuamides. The limitations could be overcome amine, and 8-hydroxymanzamine (134) also showed anti-HIV-1 1545 1502 μ similar to that of any other peptide. The route of administration activity at EC50 values of 4.2, 1.6, 2.3, and 0.6 M, respectively 1546 306 1503 should be intravenous to limit the permeation factor (Table S1). (Figure 47). 1547 f47 1504 Microspinosamide (130) was isolated from the Indonesian ADMET predictor indicates that manzamine A (132) violates 1548 1505 sponge Sidonops microspinosa. The peptide contains 13 amino two criteria of the Lipinski guidelines. This compound showed 1549 1506 acid residues. Both organic and aqueous extracts showed anti- low metabolic clearance, good oral bioavailability (20.6%), and 1550 1507 HIV-1 activity. It showed anti-HIV-1 activity at a concentration long half-life from the oral and IV pharmacokinetic studies 1551 μ 299 1508 of 0.12 M. Homophymine A, a new anti-HIV-1 compound, conducted in rats. Manzamine A (132) has a good acid solubility, 1552 306 1509 was isolated from the Homophymia sp. It possessed cytopro- which suggests that it readily dissolves in the stomach. Hence, 1553 1510 tective activity against the infection of HIV-1 at an IC50 value of this could be considered as a potentially good candidate for 1554 300 f45 1511 0.075 μM(Figure 45). clinical assessments and further development (Table S1). 1555 1512 ADMET predictor shows that microspinosamide (130) Manadomanzamines A (135) and B (136) were isolated from 1556 1513 violates three criteria of the Lipinski guidelines. In addition, it the Indonesian sponge Acanthostrongylophora sp. Manadomanz- 1557 1514 also shows low permeability, low flexibility, and a low tendency to amines A (135) and B (136) and xestomanzamine A (137) 1558 1515 permeate the cell membranes. However, the interesting fact showed activity against HIV-1 at EC50 values of 11.5, 27.0, and 1559 1516 about microspinosamide (130) is that its structure could 40.5 μM, respectively. These also exhibited activities against 1560 307 1517 incorporate 13 amino acid residues along with numerous AIDS opportunistic fungal infections and HIV-1 (Figure 48). 1561 f48 1518 uncommon amino acids, and this is the first natural peptide ADMET predictor shows that manadomanzamines A (135) 1562 299 1519 that includes a β-hydroxy-ρ-bromophenylalanine residue. and B (136) violate two criteria of the Lipinski guidelines 1563 1520 Hence, it is always a challenge to develop such molecules. whereas the xestomanzamine A (137) does not violate any of the 1564 1521 Different techniques can be adopted to synthesize such criteria. The structures of manadomanzamines A (135) and B 1565 1522 compounds and to reduce their limitations (Table S1). (136) are the unprecedented rearrangement of the skeleton of 1566

Z DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 44. Callipeltin A (125) isolated from Callipelta, neamphamide A (126) isolated from Neamphius huxleyi, mirabamide A (127), celebeside A (128),450 and theopapuamide B (129)450 isolated from Siliquariaspongia mirabilis.

Figure 46. Dragmacidin F (131) isolated from the marine sponge Figure 45. Microspinosamide (130) isolated from the Indonesian belonging to the Halicortex genus from the southern coast of Ustica sponge Sidonops microspinosa. Island in Italy.

AA DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 50. Isoaaptamine (141) and aaptamine (142) isolated from the sponge Aaptos aaptos. Figure 47. Manzamine A (132), 6-deoxymanzamine X (133), and 8- hydroxymanzamine (134) isolated from Haliclona sp.

Figure 51. Structures of petrosin (143) and petrosin A (144).

Figure 48. Manadomanzamines A (135) and B (136) and xestomanz- amine A (137) isolated from the Indonesian sponge Acanthostrongylo- phora sp.

307 1567 manzamine. Hence, these compounds could be considered 1568 similar to manzamine and could be dealt with accordingly (Table 1569 S1). 1570 Batzelladines A−E, which are also known to possess anti-HIV- Figure 52. Cyanthiwigin B (145) isolated from the Jamaican sponge 308 1571 1 activity, were isolated from the sponges belonging to the Epipolasis reiswigi. 1572 Batzella and Monanchora genera. These are known to be the first 1573 small-molecular-weight (between 400 and 800) HIV-1 entry 1574 inhibitors. They were shown to inhibit gp120−CD4 inter- 308 1575 action. Crambescidins 800 (138) and 826, also isolated from 1576 sponges from the Batzella and Monanchora genera as well as from 1577 starfishes, and fromiamycalin, isolated from starfishes and some 1578 synthetic batzelladine analogues, also showed similar anti-HIV-1 1579 activity by inhibiting HIV-1 envelope-mediated fusion. Cram- 1580 bescidine 800 (138) had activity against HIV-1 with an EC50 1581 value of 0.04 μM. Similarly, ptilomycalin A (139), isolated from 1582 the sponge Monanchora unguifera and starfishes, is also known to Figure 53. Structures of haplosamates A (146) and B (147). μ 1583 exhibit anti-HIV-1 activity at an EC50 value of 0.011 M; 1584 meanwhile, batzelladine C (140) showed inhibition at an EC50 of 1585 7.7 μM. Comparatively, batzelladine and ptilomycalin show guidelines whereas batzelladine C (140) does not violate any. In 1590 1586 potent activity against AIDS opportunistic infections and HIV-1 addition, ptilomycalin A (139) shows low flexibility and a low 1591 309 f49 1587 (Figure 49). tendency to permeate into cell membranes whereas crambesci- 1592 1588 ADMET predictor shows that ptilomycalin A (139) and din 800 (138) exhibits low permeability, low flexibility, and less 1593 1589 crambescidin 800 (138) violate three criteria of the Lipinski tendency to permeate the cell membranes. Batzelladine C (140) 1594

Figure 49. Ptilomycalin A (139), isolated from the sponge Monanchora unguifera, and crambescidine 800 (138) and batzelladine C (140) isolated from the Batzella and Monanchora genera.

AB DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

19.4. Diterpenes In 1992, four cyanthiwigins were isolated from Epipolasis reiswigi, 1618 a Jamaican sponge. These included cyanthiwigins A, B (145), C, 1619 and D. Among these, only cyanthiwigin B is known to possess 1620 μ moderate anti-HIV-1 activity at an EC50 value of 42.1 M. This 1621 may be due to the C-8 ketone group, which is only present in 1622 cyanthiwigin B and is absent in the other three compounds 1623 312 (Figure 52). 1624 f52 ADMET predictor shows that cyanthiwigin B (145) does not 1625 Figure 54. Structure of clathsterol (148). violate any of the Lipinski guidelines. The structure looks simple 1626 to prepare, and because it does not have any limitations, this 1627 could be another likely candidate to be considered for preclinical 1628 trials and further development (Table S1). 1629 19.5. Sulfated Sterols Two sulfated sterols isolated from the species Xestospongia and 1630 fi Figure 55. Structure of polyacetylenetriol (149). the other from an unidenti ed haplosclerid sponge are known to 1631 possess the unusual steroidal sulfamate esters−haplosamates A 1632 (146) and B (147), which showed inhibition towards HIV-1 1633 μ integrase at IC50 values of 50 and 15 g/mL, respectively. The 1634 sulfamate group present in the haplosamates is responsible for 1635 313 the inhibition of HIV-1 integrase (Figure 53). 1636 f53 Clathsterol (148) is an active and novel sulfated sterol isolated 1637 Figure 56. Structure of dehydrofurodendin (150). from the Red Sea sponge Clathria sp. that showed inhibition 1638 314 against HIV-1 reverse transcriptase at 10 μM(Figure 54). 1639 f54 19.6. Miscellaneous Antivirals Possessing Anti-HIV Activity Polyacetylenetriol (PAT) (149), isolated from the marine 1640 sponge Petrosia sp., showed selective inhibition against DNA- 1641 and RNA-dependent DNA polymerase activities of the retroviral 1642 μ reverse transcriptase at an IC50 value of 0.95 M. PAT is 1643 considered to be a reversible, noncompetitive inhibitor and is 1644 known to interfere with the catalytic steps of the viral DNA 1645 315 polymerization (Figure 55). 1646 f55 A new C22 furanoterpene isolated from the Madagascan 1647 sponge, Lendenfeldia, is designated as dehydrofurodendin (150), 1648 which showed inhibition against HIV-1 reverse transcriptase 1649 associated DNA- and RNA-directed DNA polymerase at IC50 1650 316 Figure 57. Structure of the repeating unit of rosacelose (151). values ranging between 3.2 and 5.6 μM(Figure 56). 1651 f56 Cimino et al. reported a new anti-HIV polysaccharide named 1652 rosacelose (151) that comprises glucose and fucose sulfate 1653 1595 shows low permeability and less flexibility. Because these isolated from the aqueous extract of the marine sponge Mixylla 1654 1596 compounds are HIV-1 entry inhibitors, limitation of permeability rosacea, which possessed a linear polysaccharide structure 1655 1597 should not be considered as a serious issue, and one should rather comprising 4,6-disulfated 3-O-glycosylated α-D-glucopyranosyl 1656 1598 concentrate on improving the limitations for further develop- and 2,4-disulfated 3-O-glycosylated α-L-fucopyranosyl residues 1657 317 1599 ment (Table S1). in a molar ratio of 3:1 (Figure 57). 1658 f57 1600 Isoaaptamine (141) and aaptamine (142) were isolated from Table 1 shows the summary of all the marine antivirals 1659 t1 1601 various sponges belonging to the Suberites, Hymenlacidon, and possessing anti-HIV-1 activity. 1660 1602 Aaptos generas. They are known to possess anti-HIV-1 activity at 1603 concentrations of 0.6 and 1.30 μM, respectively. The potency of 20. MARINE DRUGS FOR THE TREATMENT OF OTHER fl 1604 this activity has been further explored through a SAR of uorine VIRAL DISEASES 1661 310 f50 1605 substitution on an indole heterocyclic system (Figure 50). 20.1. Hepatitis B 1606 ADMET predictor predicts that isoaaptamine (141) and 1607 aaptamine (142) do not violate any of the Lipinski guidelines. The marine polysaccharide 911 that is isolated from alginate is 1662 1608 This could be a good indicator that they might not be involved in known to prevent the replication of hepatitis B virus (HBV) by 1663 1609 any potential side effects or problems, and perhaps they could be inhibiting the activity of HBV DNA-polymerase, improving the 1664 318 1610 considered as potential candidates for further development host-cell immune function. Wu et al. reported that the DNA 1665 1611 (Table S1). replication of the duck HBV could be inhibited by the oyster 1666 1612 Petrosin (143) and petrosin A (144) are bisquinolizidine polysaccharides by reducing the duck HBV−DNA content from 1667 319 1613 alkaloids isolated from the Indian marine sponge Petrosia similis, the serum, thus showing anti-HBV in vivo effects. Guan 1668 fi 1614 which showed inhibition against HIV-1 replication at IC50 values identi ed that the polymeric mannuronic acid sulfate could 1669 μ ff 1615 of 41.3 and 53 M, the recombinant reverse transcriptase at IC50 e ectively reduce the antigen levels and the DNA levels of the 1670 1616 values of 10.6 and 14.8 μM, and the formation of giant cells at HBV in duck blood, thus improving the cellular and humoral 1671 μ 311 320 f51 1617 IC50 21.2 and 36.1 M, respectively (Figure 51). immune function. The replication of HBV is also known to be 1672

AC DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review Table 1. Summary of the Marine Organisms Showing Anti-HIV-1 Activity

compound type source cellular target activity ref ‴ μ 8,4 -dieckol phlorotannins Ecklonia cava reverse transcriptase HIV-1 IC50 5.3 and 0.5 M 227, 228, 8,8′ -bieckol and231 ′ μ 6,6 -bieckol entry and reverse transcriptase HIV-1 IC50 1.07 M μ diphlorethohydroxycarmalol phlorotannins Ishige okamurae reverse transcriptase IC50 9.1 and25.2 M 232 μ N-carboxymethyl chitosan chitin shells of shrimps & reverse transcriptase HIV-1 IC50 0.02 M 236 and 237 polysaccharide crabs sulfated glucuronogalactan sulfated Schizymenia dubyi syncytial formation and reverse HIV-1 5 μg/mL 247 polysaccharides transcriptase sea algal extract (SAE) citrate buffer extract Schizymenia pacifica reverse transcriptase 9.5 × 103 IU/mL 248 and249 fucan A fucans Dictyota mertensii reverse transcriptase HIV-1 1.0 mg/mL 251 fucan B Spatoglossum 0.5 μg/mL schroederi − μ naviculan sulfated Navicula directa cell cell fusion IC50 0.24 M 253 polysaccharide laminaran polysaccharide Kelp reverse transcriptase HIV-1 50 μg/mL 255

galactan sulfate polysaccharide Agardhiella tenera cell binding HIV-1 and HIV-2 IC50 0.5 and 256 0.05 μg/L μ calcium spirulan (Ca-SP) sulfated Arthrospira platensis viral replication HIV-1 ED50 11.4 and 2.3 g/mL 259 polysaccharide − μ (GRFT) lectin Griffithsia sps. cell cell fusion HIV-1 EC50 0.000043 M 267 β − μ CVL -galactose specific Chaetopterus cytopathic effects EC50 0.0043 0.057 M 268 lectin variopedatus − μ cell cell fusion EC50 0.073 M μ CGL lectin Crenomytilus syncytium formation EC50 27.9 g/mL 269 grayanus

DTL and DTL-A lectins Didemnum ternatanum syncytium formation EC50 0.002 and 0.36 269 μg/mL μ SVL-2 GlcNAc-specific Serpula vermicularis syncytium formation EC50 0.15 g/mL 223 lectin and269 μ Leu-Leu-Glu-Tyr-Ser-Ile peptides Crassostrea gigas protease IC50 0.02 M 270 μ Leu-Leu-Glu-Tyr-Ser-Leu IC50 0.015 M μ polyphemusin II peptide Limulus polyphemus viral adsorption preceding HIV-1 EC50 2.6 M 272 Tachypleus tridentatus reverse transcription and273 macrolactin-A lactone marine bacteria replication 10 μg/mL 274

Da-1 diterpenes Dictyota menstrualis replication HIV-1 EC50 40 and 70 275 μM μ AcDa-1 reverse transcriptase IC50 10 and 35 M − μ equisetin phomasetin acyl tetrameric acid Fusarium heterosporum integrase IC50 7 20 M 276 − μ thalassiolins A C sulfated flavone Thalassia testudinum integrase IC50 30 M 277 glycosides μ didemnaketals A and B spiroketals Didemnum sp. protease IC50 2 and 10 M 278 μ cyclodidemniseriol sulfated serinolipid Didemnum guttatum integrase IC50 60 g/mL 279 trisulfate α μ lamellarin 20-sulfate alkaloid Arabian Sea ascidian integrase IC50 16 M 281 μ avarol sesquiterpene Disidea avara replication HIV-1 IC50 0.3 M 283 hydroquinone

curcuphenols a, c, j, and r sesquiterpene Didiscus oxeata, D. flavus, reverse transcriptase, protease, EC50 31.2, 29.2, 18.4, 286 phenol Myrmekioderma styx, Epipolasis sps. viral entry and 18.2 μM μ papuamides A and B cyclic Theonella swinhoei T. mirabilis viral entry and phospholipids HIV-1 EC50 0.003 M 293 depsipeptides μ callipeltin A cyclic depsipeptide Callipelta genus cytotoxicity ED50 0.007 M 295 μ neamphamide A cyclic depsipeptide Neamphius huxleyi cytoprotective EC50 0.028 M 296 μ mirabamide A cyclic depsipeptide Siliquariaspongia mirabilis fusion IC50 0.04 and 0.14 M 297 μ celebeside A and theopapuamide B cyclic Depsipeptide S. mirabilis entry IC50 2.13 M 298 μ IC50 0.99 M μ microspinosamide cyclic depsipeptide Sidonops microspinosa cytopathic effect HIV-1 EC50 0.12 M 299 μ homophymine A cyclic depsipeptide Homophymia sps. cytoprotective effect IC50 0.075 M 300 μ dragmacidin F alkaloid Halicortex Genus syncytia formation EC50 0.9 M 301 μ manzamine A alkaloid Haliclona sps. unknown EC50 4.2 M 304 and306

manadomanzamines A and B alkaloid Acanthostrongylophora sps. unknown EC50 11.5, 27.0, and 307 xestomanzamine A 40.5 μM μ batzelladine C alkaloid Batzella and Monanchora gp120-CD4 interaction EC50 7.7 M 309 genera fusion μ icrambescidin 800 EC50 0.04 M μ ptilomycalin A alkaloid Monanchora unguifera unknown EC50 0.011 M 309 μ isoaaptamine aaptamine alkaloids Aaptos aaptos unknown EC50 0.6 M 310

AD DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review Table 1. continued μ EC50 1.3 M μ petrosin bisquinolizidine Petrosia similis replication IC50 41.3 & 53 M 311 alkaloids μ petrosin A reverse transcriptase IC50 10.6 and 14.8 M μ cyanthiwigins B diterpene Epipolasis reiswigi unknown EC50 42.1 M 312

haplosamates A and B sulfated sterols Xestospongia sp. integrase HIV-1 IC50 50 and 15 313 μg/mL clathsterol sulfated sterol Clathria sp. reverse transcriptase 10 μM 314 μ polyacetylenetriol polymer Petrosia sp. reverse transcriptase IC50 0.95 M 315 − μ dehydrofurodendin C22 furanoterpene Lendenfeldia reverse transcriptase IC50 3.2 5.6 M 316

Figure 58. Structure of sulfated polymannuroguluronate (SPMG) (152). Figure 61. Structures of calyceramides A (159), B (160), and C (161).

Figure 59. Structures of discorhabdins A (153) and C (154) and dihydrodiscorhabdin C (155).

1673 indirectly inhibited by the sulfated polymannuroguluronate 1674 (SPMG) (152) isolated from the brown algae by improving the 261,318 Figure 62. Structures of weinbersterols A (162) and B (163) and f58 1675 cellular and humoral immune functions (Figure 58). stachyflin (164). 20.2. HCV 1676 Discorhabdins A (153) and C (154) and dihydrodiscorhabdin C 1677 (155) isolated from the Latrunculia genus of the Alaskan sponge 1678 species exhibited anti-HCV activity at EC90 concentrations of 321,322 f59 1679 <10 μM(Figure 59). 20.3. HPV 1680 Buck et al. established that carrageenans could inhibit the HPV 1681 infection process, and the antiviral effect is known to be better in 1682 the ι-carrageenan (156) isolated from Eucheuma denticulatum 323 1683 compared to λ-(157) and κ-carrageenans (158). Carra- 1684 geenans bind to the HPV capsid, inhibiting the viral adsorption Figure 63. Structure of KCO (165). 1685 process along with the viral-entry and viral-uncoating process. 1686 The mechanism involved in the inhibition of HPV is known to be f60 1687 independent of heparin sulfate after the viral adsorption (Figure 325 324 and B. The active sulfated calyceramides A−C(159−161) 1692 f60 1688 60). isolated from the marine sponge Discodermia calyx are known to 1693 fl 20.4. In uenza Virus inhibit the IAV neuraminidase inhibitors. Calyceramides A−C 1694 1689 Extracellular sulfated polysaccharides isolated from the marine (159−161) are known to inhibit the neuraminidase from 1695 μ 1690 microalgae Cochlodinium polykrikoides, A1 and A2, are known to Clostridium perfringens at IC50 values of 0.4, 0.2, and 0.8 g/mL, 1696 326 1691 inhibit the cytopathic effects of the influenza virus (IAV) types A respectively (Figure 61). 1697 f61

Figure 60. Structures of ι-(156), λ-(157), and κ-carrageenans (158).

AE DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 64. Structures of dextran sulfate (166) and ulvan (167).

Figure 68. Structures of halovirs A (172), B (173), C (174), D (175), and E (176).

Figure 65. Structures of oligomeric mannuronic acid (OM) (168) and polymannuronic acid propyl sulfate (PMS) (169).

Figure 69. Structures of eudistomins (177) and didemnins (178).

Figure 66. Structure of the carrageenan oligosaccharide CO-1 (170).

Figure 70. Structure of heparin (179).

Figure 71. Structure of μ-carrageenan (180).

Figure 67. Structure of fucoidan (171). from the fungus Stachybotrys sp. RF-7260, is known to inhibit 1701 influenza A virus (H1N1) at an inhibitory concentration of 0.003 1702 326 1698 Weinbersterols A (162) and B (163), isolated from the μM, which is known to be better than the other anti-H1N1 drugs 1703 328 1699 sponge Petrosia weinbergi, are known to inhibit the mouse such as zanamivir and amantadine. Stachyflin (164) possesses 1704 327 1700 influenza virus. A novel terpenoid stachyflin (164), isolated a novel cis-fused decalin along with a pentacyclic moiety and is 1705

AF DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

could enter into the host cells, inhibiting the protein translation 1756 and mRNA transcription after the internalization, thereby 1757 332 preventing the viral replication (Figures 60 and 66). 1758 f66 20.5. Respiratory Syncytial Virus

The isolation of two extracellular sulfated polysaccharides, A1 1759 and A2 from Cochlodinium polykrikoides, was reported by Hasui 1760 et al. and showed inhibition on the cytopathic effects against RSV 1761 325 types A and B growing on Hep-2 cells. 1762 20.6. Dengue Figure 72. Structures of mycalamide A (181), mycalamide B (182), 4- 342 methylaaptamine (183), and hamigeran B (184). A fucan polysaccharide, fucoidan (171) isolated from 1763 Cladosiphon okamuranus comprising the sulfated fucose units 1764 and glucuronic acid, showed inhibition of BHK-21 cells in 1765 1706 known to exhibit antiviral activity by inhibiting the viral host-cell DENV-2 with little effect on the other three types, DENV-1, -3, 1766 329,330 343 f62 1707 membrane and envelope (Figure 62). and -4. Talarico and co-workers reported ι-(156) and λ- 1767 1708 Tang et al. showed that the low-molecular-weight (MW) carrageenans (157) that interfere with the internalization and 1768 fi 344 1709 carrageenans along with their derivatives exhibited signi cant adsorption of the DENV-2 host cells. The mechanism that is 1769 fl 1710 inhibition activity against in uenza virus in mice (FM1-induced 1770 331 involved in inhibition is thought to be due to the interference of 1711 pulmonary edema). Wang and co-workers reported the carrageenans on the subsequent uncoating and release of DENV 1771 1712 inhibition of IAV replication both in vitro and in vivo by the from the endosomes. ι-Carrageenan (156) exhibited inhibition 1772 κ 1713 low MW carrageenan oligosaccharide KCO ( -carrageenan through direct interaction with the viral membrane glycoprotein 1773 344−346 1714 oligosaccharide) (165) along with their sulfated derivatives. E (gE). Talarico et al. found that the ι-carrageenan (156) 1774 fi 1715 The sulfate content, speci c sugar linkage, and certain sugar exhibited inhibition of DENV replication in both mammalian 1775 344 1716 length of KCO (165) are known to be essential for the anti-IAV and mosquito cells, affecting the potential targets within the 1776 κ 347 1717 activity of the -carrageenan (158) oligosaccharide. KCO (165) DENV host cells (Figures 60 and 67). 1777 f67 1718 inhibits the replication phase of the IAV life cycle following viral 20.7. Herpes Simplex Virus (HSV) 1719 internalization and prior to the release of the virus. κ- 1720 Carrageenan (158) saccharide, being the most active, has a Two novel exopolysaccharides EPS-1 and EPS-2, isolated from 1778 1721 molecular weight of 1−3 kDa with sulfate content 0.8−1.0 mol/ the marine bacteria Geobacillus thermodenitrificans and Bacillus 1779 332,333 f63 1722 mol of disaccharide (Figures 60 and 63). licheniformis, respectively, are known to inhibit HSV-2 replication 1780 348,349 1723 Lüscher-Mattli and Glück reported the anti-IAV activity of at 200 and 300 μg/mL. A1, an extracellular sulfated 1781 1724 dextran sulfate (166) through the inhibition of the IAV fusion polysaccharide isolated from a marine microalgae, Cochlodinium 1782 325 1725 with cell membranes and suppression of the viral replication in polykrikoides, showed activity against HSV-1. Fucoidan (171), 1783 334 1726 vivo. Ivanova et al. reported the inhibitory effect on IAV by a sulfated polysaccharide isolated from Fucus vesiculosus, a brown 1784 1727 ulvan polysaccharides (167) isolated from the green algae whose seaweed, is known to inhibit the replication of HSV-1 and HSV-2 1785 335 350,351 1728 effect is known to be strain-specific and dose-dependent. viruses. Calcium-spirulan (Ca-SP), a sulfated polysacchar- 1786 1729 Akamatsu et al. reported a new type of fucose polysaccharide, ide isolated from Arthrospira platensis, a marine blue−green alga, 1787 1730 MC26, isolated from the brown seaweed that is known to possess is also known to inhibit the replication of HSV-1 and influenza- 1788 336 259 1731 excellent anti-IAV effects in vitro and in vivo. Zhang et al. A. 1789 1732 reported the inhibition activity of marine polysaccharides Naviculan, isolated from Navicula directa,isasulfated1790 1733 isolated from Perna viridis against the replication of IAV in polysaccharide that inhibited the early viral replication stages at 1791 ff μ 253 1734 MDCK cells and its additive e ect on the ribavirin anti-IAV IC50 values ranging between 7 and 14 g/mL. Halovirs A 1792 1735 actions, suggesting further investigation on these marine (172), B (173), C (174), D (175), and E (176) isolated from the 1793 337 f64 1736 polysaccharides as anti-IAV agents (Figure 64). marine fungus Scytidium species showed potent antiviral activity 1794 1737 A low-molecular-weight (<5 kDa) oligomeric mannuronic against HSV-1 and HSV-2 at ED50 values 1.1, 3.5, 2.2, 2.0, and 3.1 1795 1738 acid (OM) (168,) which is an oligosaccharide derivative of μM, respectively. Halovir A also inhibited the replication of HSV- 1796 1739 polymannuronic acid polysaccharide, showed good activity 1 and HSV-2 at an ED50 of 280 nm. The mechanism of action is 1797 338 1740 against H1N1 influenza A virus both in vitro and in vivo. not yet known but is thought to be due to membrane 1798 352 1741 Guan reported another polymannuronic acid derivative, destabilization (Figures 67and 68). 1799 f68 353 1742 polymannuronic acid propyl sulfate (PMS) (169), prepared by Eudistomins (177) and their related β-carboline alkaloids 1800 1743 the propyl modification and sulfation of polymannuronic acid isolated from the tunicate Eudistoma olivaceum showed inhibition 1801 339 354 355 1744 polysaccharide, which showed an inhibitory effect on against HSV-1 and HSV-2. Didemnins (178) isolated from 1802 1745 neuraminidase activity of IAV along with alleviating pneumonia Trididemnum sp. of tunicates are cyclic depsipeptides that 1803 1746 symptoms effectively caused by influenza A viral infection, showed in vivo and in vitro antiviral activities against HSV-1 1804 340 356 f65 1747 reducing the mortality rate in mice (Figure 65). (Figure 69). 1805 f69 1748 Kim et al. reported p-KG03, a sulfated polysaccharide isolated Studies indicated the use of heparin polysaccharides and low- 1806 1749 from the marine microalga Gyrodinium impudium, which showed molecular-weight heparin (179) as natural inhibitors of HSV-1 1807 357,358 1750 maximum inhibition activity against IAV infection targeting the that require a unique sulfation moiety. The marine 1808 1751 viral internalization and adsorption, preventing the viral heparinoid polysaccharides are considered to be structurally 1809 341 1752 replication. Wang et al. reported a low-molecular-weight κ- similar to heparin (179), possessing glycosaminoglycan (GAG)- 1810 1753 carrageenan (158) oligosaccharide that is known to effectively like biological properties, and include ulvans (167), alginates, 1811 332,333 1754 inhibit the IAV replication both in vitro and in vivo. It was and their sulfated derivatives along with chitosan sulfate and 1812 1755 also noted that the carrageenan oligosaccharide CO-1 (170) dextran sulfate. Recent studies indicated the cell-surface 1813

AG DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Figure 73. HIV drugs in late stage development: GS 7340 (185),451 DPC 083 (186), SCH-C (187), S-1360 (188), T-1249 (189), MK-1439 (190),452 and S/GSK1265744 (191).453

1814 heparinoid sulfate proteoglycans as the initial receptors of HSV-1 Perry et al. reported the isolation of mycalamide A (181) and B 1845 359−361 1815 and HSV-2. Heparinoid polysaccharides are known to (182) from the New Zealand sponge Mycale in the year 1988 that 1846 1816 prevent the viral binding to the cell surface by interacting with the inhibited herpes simplex virus type I at a concentration of 5 ng/ 1847 1817 positively charged regions of the cell-surface glycoproteins disc. Of the two, mycalamide B (182) was found to be more 1848 359 − f70 1818 (Figures 64 and 70). potent at a concentration of 1 2 ng/disc. 4-Methylaaptamine 1849 1819 Yu et al. studied the inhibitory actions of the scallop skirt GAG (183) isolated from the marine sponge Aaptos sp. showed anti- 1850 μ 1820 (SS-GAG) on HSV-1 at various concentrations with significant HSV-1 activity at an EC50 of 2.4 M and was found to be more 1851 μ 1852 1821 in vitro effects, and the antiviral effect of SS-GAG is known to potent than acyclovir (83) [EC50 8.6 M]. Dragmacidin F (131), 362 a bromoindole alkaloid isolated from the marine sponge 1853 1822 increase gradually with prolonged duration of action. Carlucci Halicortex, showed antiviral activity against HSV-1 at an EC 1854 1823 et al. identified the firm binding of λ-carrageenan (157) to HSV, 50 of 96 μM. Hamigeran B (184) isolated from the marine sponge 1855 1824 leading to the virion inactivation, thereby inhibiting the HSV 363 Hamigera tarangaensis also showed inhibition against herpes 1856 1825 replication. The studies also suggested the structural changes 282 363,364 virus (Figures 25, 46, and 72). 1857 f72 1826 of HSV-glycoproteins gB and gC by carrageenan. Further it 1827 was also noted that cyclized μ (180)-/ι-carrageenan (156) 21. IN THE PIPELINE: HIV AND HCV DRUGS UNDER 1828 isolated from Gigartina skottsbergii also showed potent antiviral DEVELOPMENT 1858 1829 effects against HSV-1 and HSV-2 during the viral-adsorption 365 f71 1830 stage (Figures 60 and 71). 21.1. HIV 1831 Harden et al. also reported the direct inactivation of HSV-2 by GS-7340 (185) also known as fumarate 1859 1832 carrageenan polysaccharides isolated from red algae at low 369 (TAF) is an anti-HIV-1 prodrug that has been patented by 1860 1833 concentrations. The virucidal activities of the carrageenan Gilead (no. WO2002008241). GS-7340 belongs to the NRTIs 1861 1834 polysaccharides are known to increase with increasing molecular 370 366 and is currently under Phase III clinical trials. It is known to 1862 1835 weight until 100 kDa. The direct virucidal activity of inhibit the reverse transcriptase enzyme, thereby preventing viral 1863 1836 carrageenans is known to be due to the formation of stable 371 − replication, and is also known as a prodrug of tenofovir. 1864 1837 carrageenan virion complex, making the binding irreversible SPI-452 is another anti-HIV-1 drug currently in Phase II 1865 fi 1838 and lling the viral envelope sites necessary for viral attachment clinical trials that has been patented by Sequoia Pharmaceuticals 1866 370 1839 to the host cells with sulfated polysaccharide preventing the (no. WO2008022345). The drug is a boosting agent that has 1867 367 1840 completion of the viral infection process. Kanekiyo et al. no antiviral properties but enhances the levels of the second drug 1868 fl 372 1841 reported that nosto an, an acidic polysaccharide isolated from taken. 1869 1842 Nostoc flagelliforme, an edible blue−green alga, showed good There are investigational NNRTIs for the treatment of HIV-1, 1870 373 374 1843 inhibitory activity against HSV-1, preventing the binding of virus namely, DPC 083 (186). DPC 083 (186) is a 1871 368 1844 to the host cells. quinazolinone derivative of efavirenz, but Bristol-Myers Squibb 1872

AH DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

373 (187), and T-1249 (189). PRO 542 could be classified under 1875 CD4-attachment inhibitors that show activity against viral 1876 377 isolates by binding to viral gp120. Schering C or SCH-C 1877 (187) belongs to the class of chemokine receptor (CCR5) 1878 378 inhibitors and has oral bioavailability. T-1249 (189)isa1879 synthetic 39-amino-acid peptide belonging to the class of HIV 1880 379,380 fusion inhibitors. S-1360 (188), a 1,3-diketone derivative, 1881 is an investigational HIV and shows anti- 1882 retroviral activity when the amino acids are substituted at the 1883 381 active site of the integrase. T-1249 (189) has oral 1884 bioavailability and is currently undergoing Phase I/II clinical 1885 373 382 studies. MK-1439 (190), an investigational oral HIV 1886 NNRTI, is currently undergoing Phase II clinical trials by 1887 383 384 Merck & Co., Inc. S/GSK1265744 (191), a HIV integrase 1888 inhibitor, is in ongoing Phase II clinical trials under 1889 385 GlaxoSmithKline (Figure 73). 1890 f73 21.2. HCV

Mericitabine (192), also known as MCB or RG7128 once 1891 bioconverted to its 5′-NTP (nucleotide triphosphate), is a HCV 1892 nucleoside inhibitor of NS5B RNA-dependent RNA polymer- 1893 386 ase. It was studied up to Phase II clinical trials, but it was not 1894 found to be as potent as Sofosbuvir and is not being developed by 1895 387 388 Roche in the U.S. or Europe. (193)isa1896 macrocyclic peptidomimetic compound that inhibits HCV NS3/ 1897 4A protease and is currently in Phase II clinical trials managed by 1898 387 389 Roche. (194) is another HCV non-nucleoside 1899 387 inhibitor that inhibits NS5b RNA polymerase. 1900 390 BI 201335 (195) is an oral HCV NS3/4A protease inhibitor 1901 that was stopped at Phase III clinical trials managed by 1902 Boehringer-Ingelheim. Similarly BI 207127 or 1903 390,391 (196), an oral HCV NS5B RNA-dependent polymerase 1904 392 inhibitor, was undergoing Phase II clinical trials. 1905 393 Merck Co. has two HCV drugs: MK-5172 (198), an oral 1906 394 NS3/4A protease inhibitor, and MK-8742 (197), an oral 1907 NS5A protease inhibitor undergoing Phase II clinical trials. MK- 1908 395 396 7009 or (199) is an investigational oral NS3/4A 1909

454 protease inhibitor that is currently undergoing Phase III clinical 1910 Figure 74. Novel HCV drugs: mericitabine (192), danoprevir 383 397 455 456 457 200 1911 (193), setrobuvir (194), BI 201335 (195), BI 207127 (196), trials. GSK2336805 ( ) is a HCV inhibitor that was 458 undergoing Phase II clinical trials under GlaxoSmithKline 1912 MK-8742 (197), MK-5172 (198), MK-7009 or vaniprevir (199), and 385 GSK 2336805 (200).459 (Figure 74). 1913 f74 21.3. Pneumonia

Merck Co. developed a pneumoconjugate vaccine V114 that is 1914 currently under Phase II clinical trials. V114 is an investigational 1915 vaccine that showed protection against pneumococcal disease 1916 398 that is caused by serotypes present in the vaccine. 1917 21.4. HBV

Gilead Sciences developed three drugs for the treatment of 1918 460 chronic HBV infectiontenofovir alafenamide (TAF), also GS- 1919 Figure 75. Structure of GS-9620 (201). 399 7340 (185), a nucleotide reverse transcriptase inhibitor that is 1920 400 currently under Phase III clinical trials; GS-4774, a therapeutic 1921 401 vaccine that is a tarmogen T cell immunity stimulator;l and 1922 402 GS-9620 (201), a toll-like receptor 7 (TLR-7) agonist  1923 400 which are under Phase II clinical trials (Figures 73 and 75). 1924 f75 21.5. HPV

Merck developed HPV vaccine V503 against HPV-related 1925 461 Figure 76. Structure of nitazoxanide (202). cancers; it is an investigational human papillomavirus (HPV) 1926 vaccine that targets nine subtypes6, 11, 16, 18, 31, 33, 45, 52, 1927 375,376 1873 never developed this potent molecule. Some of the entry and 58. V503 is being evaluated for the prevention of HPV, which 1928 398 1874 inhibitors that are in investigation include PRO 542, Schering C is currently under review. 1929

AI DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

Table 2. Summary of the Marine Organisms Possessing Antiviral Activity

compound type source target activity ref μ discorhabdins A and C alkaloid Latrunculia HCV EC90 <10 M 321, 322 dihydrodiscorhabin C ι-carrageenan linear sulfated galactans Eucheuma denticulatum HPV capsid unknown 323, 324 A1 and A2 sulfated polysaccharides Cochlodinium polykrikoides influenza virus and unknown 325 RSV − fl calyceramides A C sulfated ceramides Discodermia calyx in uenza IC50 0.4, 0.2, and 0.8 326 neuraminidase μg/mL weinbersterols A and B sulfated tetrahydroxy Petrosia weinbergi influenza virus unknown 326, 327 steroids stachyflin terpenoid Stachybotrys influenza A virus 0.003 μM 328, 329, 330 ulvan polysaccharides polysaccharide green algae influenza virus unknown 335 MC26 fucose polysaccharide brown seaweed influenza virus unknown 336 p-KG03 sulfated polysaccharide Gyrodinium impudium influenza virus unknown 341 fucoidan fucan polysaccharide Cladosiphon okamuranus DENV unknown 342, 343 EPS-1 and EPS-2 exopolysaccharides Geobacillus thermodenitrificans and Bacillus HSV 200 and 300 μg/mL 348, 349 licheniformis A1 sulfated polysaccharide Cochlodinium polykrikoides HSV-1 unknown 325 fucoidan sulfated polysaccharide Fucus vesiculosus HSV-1 HSV-2 unknown 350, 351 replication calcium spirulan sulfated polysaccharide Arthrospira platensis HSV-1 and influenza unknown 259 − μ naviculan sulfated polysaccharide Navicula directa HSV replication IC50 7 14 g/mL 253 stages − halovirs A E peptides Scytidium HSV-1 and HSV-2 ED50 1.1, 3.5, 2.2, 2.0, and 352 3.1 μM eudistomins β-carboline alkaloids Eudistoma olivaceum HSV-1 and HSV-2 unknown 354 didemnins cyclic depsipeptides Trididemnum HSV-1 unknown 355, 356 μ- and ι-carrageenan linear sulfated galactans Gigartina skottsbergii HSV-1 and HSV-2 unknown 365 nostoflan acidic polysaccharide Nostoc flagelliforme HSV-1 unknown 368 mycalamide A and B tetrahydropyran Mycale HSV-1 5 ng/disc 282 trioxadecalins μ 4-methylaaptamine alkaloid Aaptos HSV-1 EC50 2.4 M 282 μ dragmacidin F bromoindole alkaloid Halicortex HSV-1 EC50 96 M 282 hamigeran B tricyclic benzo-fused Hamigeran tarangaensis HSV unknown 282 hydrindanes

21.6. Norovirus 21.9. Shingles 1930 Romark Laboratories developed nitazoxanide (202), a thiazolide Merck Co. developed a herpes zoster inactivated VZV vaccine, 1953 1931 agent for the treatment of viral gastroenteritis, and conducted a V212, that is being evaluated for the prevention of herpes zoster 1954 1932 double-blind placebo-controlled clinical trial for the evaluation of (HZ) and HZ-related complications in immunocompromised 1955 398 1933 its activity against norovirus, adenovirus, or rotavirus. Nitazox- subjects, currently under Phase III clinical trials. 1956 1934 anide (202) is known to interfere with the enzyme-dependent 1935 transfer reactions of pyruvate ferredoxin oxidoreductase [PFOR] 22. CONCLUSION 1936 necessary for the anaerobic energy metabolism, preventing the Natural products continue to provide an excellent source of new 1957 403 f76 1937 synthesis of the viral proteins (Figure 76). leads for the development of anti-HIV agents. A summary of the 1958 21.7. Influenza marine organisms possessing anti-HIV-1 activity and other 1959 antiviral activities are shown in Tables 1 and 2. As per the Lipinski 1960 t2 1938 Roche developed RG7745, a human monoclonal antibody that is guidelines, the “Lipinski rule of five” states that the compound 1961 1939 designed to neutralize the influenza A virus against a wide range should have a molecular weight <500, a log P value not more than 1962 1940 of strains. RG7745 binds to the epitope on the influenza A 5, hydrogen bond donors of <5, and hydrogen bond acceptors of 1963 1941 hemagglutinin stalk region that is highly conserved and is 407 404 <10 for it to have oral bioavailability and better absorption. 1964 1942 currently under Phase II clinical trials. GlaxoSmithKline However, most oral drug formulations available in the market fail 1965 1943 developed relenza (zanamivir), a for the in at least one Lipinski guideline that, for example, includes 1966 1944 treatment of influenza that is currently under Phase III clinical 405 didanosine, which exceeds the log P value and yet is available as 1967 1945 trials. Nitazoxanide (202), a broad-spectrum antiviral, is in 408 406 chewable tablets. Zalcitabine (which is now rarely used for the 1968 1946 Phase III clinical trials for the treatment of influenza. treatment of HIV) also fails in one Lipinski guideline by 1969 21.8. RSV 409 exceeding the log P value and is available in tablet form. There 1970 1947 Gilead developed GS-5806, a fusion inhibitor for the treatment of are many such examples (see Table S4). 1971 1948 respiratory syncytial virus (RSV) that is currently under Phase II All the absorption criteria mentioned in the Supporting 1972 1949 clinical trials. GS-5806 blocks RSV replication by inhibiting the Information are not followed by many of the FDA-approved 1973 400 1950 RSV F-mediated fusion of the viral RNA. GlaxoSmithKline drugs. Most drugs fail in at least two to three criteria and yet are 1974 1951 developed a pediatric recombinant viral vector vaccine for the considered as drugs favored to treat HIV-1. Similarly there are 1975 405 1952 treatment of RSV that is currently in Phase I clinical trials. compounds isolated from the marine sources that are not 1976

AJ DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

1977 different to these kinds of drugs. These compounds could be Biographies 2035 1978 synthesized as oral formulations and are inexpensive to formulate 1979 based on their structures. Some include avarol (114), 1980 curcuphenol (116) and its analogues a (117), c (118), j (119), 1981 and r (120), manzamine A (132), manadomanzamines A (135) 1982 and B (136), xestomanzamine A (137), crambescidin 800 (138), 1983 ptilomycalin A (139), batzelladine C (140), isoaaptamine (141), 1984 aaptamine (142), and cyanthiwigin B (145) that could be 1985 considered for syntheses in the treatment of HIV-1. The same 1986 could be said in the case of distribution, metabolism, and toxicity 1987 criteria (see Supporting Information). 1988 All the information discussed above is only a prediction (from 1989 ADMET predictor), and hence, the drugs isolated from the 1990 marine sources need to undergo in vivo assays, advanced 1991 toxicological evaluation, and clinical trials to further strengthen 1992 the results and validate safety and efficacy profiles. Although 1993 some of the drugs fail in many criteria, they could still be adjusted Vedanjali Gogineni received her M.S. in Pharmaceutical Chemistry from 2036 1994 or altered to better treat the disease. Any further progress could Fairleigh Dickinson University, New Jersey, and her Bachelor’s degree 2037 1995 be made only when the compounds from the marine sources can from Jawaharlal Nehru Technological University, India. In 2011, she 2038 1996 undergo further tests and assays. joined as a Visiting Scholar in the Department of Pharmacognosy, 2039 1997 The major challenges involved in natural product drug University of Mississippi, with Professor Mark Hamann. In 2013, she 2040 1998 development are drug resistance, long drug-development joined the graduate program in the Department of Biomolecular 2041 1999 processes, and sometimes toxic side effects. Many of the Sciences, Division of Medicinal Chemistry, University of Mississippi, 2042 2000 sponge-derived compounds have shown toxic effects. This where she is currently completing her Ph.D. degree with Professor 2043 2001 could potentially be solved by applying biochemical technologies Stephen J. Cutler. Her research interests are focused on isolation and 2044 2002 such as combinatorial biosynthesis, synthetic biology, metabolic characterization of psychoactive medicinal plants. 2045 2003 engineering, medicinal chemistry, and post-genomic techni- 223,410 2004 ques. 2005 When the virus becomes resistant to one drug, then it is not 2006 possible to treat that virus with any other naturally occurring 411 2007 derivative with similar activities against the virus. So for the 2008 discovery of new drugs, different derivatives belonging to a 2009 common class synthesized by multiple organisms could be a 2010 solution. 2011 Identifying, cloning, and modifying gene expression using 2012 synthetic biology are some of the techniques used to combat the 223 2013 large-scale production problems. Therefore, understanding 2014 the biology and the natural living conditions that affect the 282 2015 growth and metabolite production of sponges is necessary.

2016 ASSOCIATED CONTENT 2046 2017 *S Supporting Information Dr. Raymond F. Schinazi, Ph.D., D.Sc., is the Frances Winship Walters Professor of Pediatrics and Director of the Laboratory of Biochemical 2047 2018 This material is available free of charge via the internet at The Pharmacology at Emory University. He serves as Senior Research 2048 2019 Supporting Information is available free of charge on the ACS Career Scientist at the Atlanta Department of Veterans Affairs and as 2049 2020 Publications website at DOI: 10.1021/cr4006318. Director of the Scientific Working Group on Viral Eradication for the 2050 2021 Parameters necessary to analyze the pharmacokinetic and NIH-sponsored Emory University Center for AIDS Research (CFAR). 2051 2022 toxic properties of the reported marine drugs and the Dr. Schinazi received his B.Sc. (1972) and Ph.D. (1976) in chemistry 2052 2023 FDA-approved drugs (PDF) from the University of Bath, England. He has authored over 500 peer- 2053 reviewed papers and 7 books and holds 92 issued U.S. patents and over 2054 2024 AUTHOR INFORMATION 120 non-U.S. national stage patents and patent applications, which have 2055 resulted in 13 New Drug Applications (NDAs). A world leader in 2056 2025 Corresponding Author nucleoside chemistry, Dr. Schinazi is best known for his pioneering work 2057 2026 *E-Mail: [email protected]. Tel.: +1-662-915-5730. Fax: on HIV and HCV drugs d4T (stavudine), 3TC (lamivudine), FTC 2058 2027 +1-662-915-6975. (emtricitabine/Emtriva), LdT (telbivudine), and most recently 2059 2028 Present Address sofosbuvir (Sovaldi), which are now approved by the FDA. He is the 2060 # founder of five biotechnology companies including Pharmasset, Inc. 2061 2029 Department of Pharmacognosy has now been changed to More than 94% of HIV-infected individuals in the US on combination 2062 2030 Department of Biomolecular Sciences, Division of Pharmacog- therapy take at least one of the drugs he invented, and it is estimated that 2063 2031 nosy, School of Pharmacy, University of Mississippi, 407 Faser his work has saved more than 6.5 million lives worldwide. His 2064 2032 Hall, University, MS 38677. contributions related to HCV are expected to have a profound positive 2065 2033 Notes impact on over 80 million people worldwide suffering from chronic 2066 2034 The authors declare no competing financial interest. infection. 2067

AK DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

(4) National Institute of Allergy and Infectious Diseases. Health & 2113 Research Topics. http://www.niaid.nih.gov/topics/Pages/default.aspx 2114 (accessed May 15, 2014). 2115 (5) Centers for Disease Control and Prevention. Morbidity and 2116 Mortality Weekly Report (MMWR). http://www.cdc.gov/mmwr/ 2117 indss_2014.html (accessed May 15, 2014). 2118 (6) Centers for Disease Control and Prevention. Morbidity and 2119 Mortality Weekly Report (MMWR). http://www.cdc.gov/mmwr/ 2120 preview/mmwrhtml/mm6029a3.htm (accessed March 10, 2012). 2121 (7) World Health Organization. Global Report: UNAIDS Report on 2122 the Global AIDS Epidemic 2012. http://www.unaids.org/sites/default/ 2123 files/media_asset/20121120_UNAIDS_Global_Report_2012_with_ 2124 annexes_en_1.pdf (accessed March 17, 2013). 2125 (8) United Nations. Political Declaration on HIV and AIDS: 2126 Intensifying Our Efforts to Eliminate HIV/AIDS. http://www.unaids. 2127 org/sites/default/files/sub_landing/files/20110610_UN_A-RES-65- 2128 2068 Dr. Mark T. Hamann is a Professor of Pharmacognosy, Pharmacology 277_en.pdf (accessed November 27, 2011). 2129 2069 and Chemistry & Biochemistry as well as a Research Professor with the (9) UNAIDS 2012 Global Report. UNAIDS World AIDS Day Report 2130 2070 National Center for Natural Products Research at the University of 2012. http://www.unaids.org/sites/default/files/en/media/unaids/ 2131 2071 Mississippi and is an Associate Member of the UMMC Cancer Center. contentassets/documents/epidemiology/2012/gr2012/JC2434_ 2132 2072 Dr. Hamann has several years experience in GMP pharmaceutical WorldAIDSday_results_en.pdf (accessed Mar 17, 2013). 2133 2073 manufacturing at Solvay Pharmaceuticals in Baudette, Minnesota, and (10) Centers for Disease Control and Prevention. HIV Surveillance 2134 − 2074 completed a Ph.D. degree in Organic/Natural Product Chemistry in Report. 2009; Vol. 21,pp179; http://www.cdc.gov/hiv/pdf/ 2135 2075 1992 at the University of Hawaii, Chemistry Department, under the statistics_2009_HIV_Surveillance_Report_vol_21.pdf (accessed No- 2136 2137 2076 guidance of the late Professor Paul Scheuer, a pioneer in the discovery vember 25, 2011). (11) Centers for Disease Control and Prevention. HIV Prevalence 2138 2077 and development of marine products. Dr. Hamann then completed EstimatesUnited States, 2006. 2008; Vol. 57, pp 1073−1076; http:// 2139 2078 Postdoctoral Studies with Prof. Bill Baker doing field studies in www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a2.htm (accessed 2140 2079 Antarctica. During his research career, Dr. Hamann has published over November 27, 2011). 2141 fi 2080 190 scienti c papers, reviews, and book chapters and currently serves as (12) Centers for Disease Control and Prevention. New CDC Analysis 2142 2081 an Associate Editor for Biochimica et Biophysica Acta, General Subjects. Reveals Strong Link Between Poverty and HIV Infection, 2010. http:// 2143 2082 His group is actively involved in the isolation, structure determination, www.cdc.gov/nchhstp/newsroom/2010/povertyandhivpressrelease. 2144 2083 and synthetic optimization of marine/terrestrial natural products and html (accessed November 27, 2011). 2145 2084 toxins with a focus on plant and invertebrate microbiomes. His group is (13) Centers for Disease Control and Prevention. HIV among Latinos. 2146 2085 currently working on the preclinical development of a small pipeline of http://www.cdc.gov/hiv/risk/racialethnic/hispaniclatinos/index.html 2147 2148 2086 natural products with activity against infectious diseases, cancer, and (accessed November 25, 2011). (14) The White House Office of National AIDS Policy. National HIV/ 2149 2087 neuropsychiatric disorders. AIDS Strategy For The United States. http://www.whitehouse.gov/ 2150 sites/default/files/uploads/NHAS.pdf (accessed November 25, 2011). 2151 2088 ACKNOWLEDGMENTS (15) Centers for Disease Control and Prevention. Epidemiologic 2152 Notes and Reports Immunodeficiency among Female Sexual Partners of 2153 2089 We are grateful to Simulations Plus (Lancaster, CA, U.S.A.) for Males with Acquired Immune Deficiency Syndrome (AIDS)New 2154 2090 providing us with the reference site license to use the software York, 1983; Vol. 31, pp 697−698; http://www.cdc.gov/mmwr/ 2155 2091 ADMET Predictor. We also thank the Virtual Computational preview/mmwrhtml/00001221.htm (accessed November 25, 2011). 2156 2092 Chemistry Laboratory that provided the ALOGPS 2.1 software (16) Grmek, M. D. In History of AIDS: Emergence and Origin of a 2157 2093 necessary to generate the log S values for the determination of Modern Pandemic; Princeton: Princeton, NJ, 1990; pp 3−186. 2158 2094 solubility. Drs. Prabhakar Reddy Polepally, Daneel Ferreira, (17) Altman, L. K. New Homosexual Disorder Worries Health 2159 ffi 2095 Ziaeddin Shariat-Madar, and Manal Nael, a graduate student (all O cials. The New York Times, [Online], May 11, 1982. http://www. 2160 2096 from the University of Mississippi), are warmly acknowledged for nytimes.com/1982/05/11/science/new-homosexual-disorder-worries- 2161 health-officials.html?pagewanted=all (accessed November 25, 2011). 2162 2097 their help with the stereochemistry and pharmacology sections. (18) Oswald, G. A.; Theodossi, A.; Gazzard, B. G.; Byrom, N. A.; 2163 2098 Pankaj Pandey, a graduate student (University of Mississippi), is Fisher-Hoch, S. P. Attempted Immune Stimulation in the ″Gay 2164 2099 being acknowledged for introducing us to the ADMET predictor. Compromise Syndrome″. Br. Med. J. 1982, 285, 1082. 2165 2100 M.T.H. is supported in part by NIH NCCAM Grant (19) Kher, U. A Name for the Plague. TIME, [Online], July 27, 1982. 2166 2101 1R01AT007318, Kraft Foods, and the Department of Bio- http://content.time.com/time/specials/packages/article/ 2167 2102 Molecular Sciences, Division of Pharmacognosy. R.F.S. is 0,28804,1977881_1977895_1978703,00.html (accessed January 30, 2168 2103 supported in part by the NIH CFAR Grant 5P30-AI-50409, 2012). 2169 2104 1RO1-MH-100999, and the Department of Veterans Affairs. (20) Culliton, B. J. Crash Development of AIDS Test Nears Goal. 2170 Science 1984, 225, 1128−1130. 2171 (21) AIDS.gov. A Timeline of AIDS. http://www.aids.gov/hiv-aids- 2172 2105 REFERENCES basics/hiv-aids-101/aids-timeline/ (accessed March 19, 2010). 2173 2106 (1) Becker, K.; Hu, Y.; Biller-Andorno, N. Infectious Diseases - A (22) Altman, L. K. Blood Supply Called Free of AIDS. The New York 2174 2107 Global Challenge. Int. J. Med. Microbiol. 2006, 296, 179−185. Times, [Online], August 1, 1985. http://www.nytimes.com/1985/08/ 2175 2108 (2) MedicineNet.com. Definition of Agent, Anti-Infective. http:// 01/world/blood-supply-called-free-of-aids.html?pagewanted=1 (ac- 2176 2109 www.medicinenet.com/script/main/art.asp?articlekey=2178 (sccessed cessed November 25, 2011). 2177 2110 November 25, 2011). (23) Amador, M. L.; Jimeno, J.; Paz-Ares, L.; Cortes-Funes, H.; 2178 2111 (3) World Health Organization. Media Centre: Fact Sheets. http:// Hidalgo, M. Progress in the Development and Acquisition of Anticancer 2179 2112 www.who.int/mediacentre/factsheets/en/#A (accessed May 15, 2014). Agents from Marine Sources. Ann. Oncol. 2003, 14, 1607−1615. 2180

AL DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2181 (24) Bergmann, W.; Feeney, R. J. Contributions to the Study of Marine (41) U.S. Food and Drug Administration. HIV/AIDS Historical Time 2248 2182 Products. XXXII. The Nucleosides of Sponges. J. Org. Chem. 1951, 16, Line 1995−1999. http://www.fda.gov/forpatients/illness/hivaids/ 2249 2183 981−987. history/ucm151079.htm (accessed February 18, 2012). 2250 2184 (25) Carroll, J.; Crews, P. In Natural Product Chemistry for Drug (42) U.S. Department of Health & Human Services. Providing Access 2251 2185 Discovery; Buss, A. D., Butler, M. S., Eds.; Royal Society of Cambridge: to Promising Therapies for Seriously Ill and Dying Patients. http:// 2252 2186 Cambridge, U.K., 2009; pp 174−195. www.fda.gov/NewsEvents/Testimony/ucm115120.htm (accessed Feb- 2253 2187 (26) North, T. W.; Cohen, S. S. Aranucleosides and Aranucleotides in ruary 18, 2012). 2254 2188 Viral Chemotherapy. Pharmacol. Ther. 1979, 4,81−108. (43) Staszewski, S.; Katlama, C.; Harrer, T.; Massip, P.; Yeni, P.; 2255 2189 (27) Ostertag, W.; Roesler, G.; Krieg, C. J.; Kind, J.; Cole, T.; Crozier, Cutrell, A.; Tortell, S. M.; Harrigan, R. P.; Steel, H.; Lanier, R. E.; Pearce, 2256 2190 T.; Gaedicke, G.; Steinheider, G.; Kluge, N.; Dube, S. Induction of G. A Dose-Ranging Study to Evaluate the Safety and Efficacy of Abacavir 2257 2191 Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Alone or in Combination with Zidovudine and Lamivudine in 2258 ̈ − 2259 2192 Cell Cultures Transformed by Friend Virus. Proc. Natl. Acad. Sci. U. S. A. Antiretroviral Treatment-Naive Subjects. AIDS 1998, 12, F197 F202. 2193 1974, 71, 4980−4985. (44) Weiss, R. A.; Wrangham, R. W. From Pan to Pandemic. Nature 2260 − 2261 2194 (28) Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St Clair, M. H.; 1999, 397, 385 386. (45) Morbidity and Mortality Weekly Report (MMWR). Nonoxynol-9 2262 2195 Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder, S. 3′- Spermicide Contraception UseUnited States, 1999, 2002; Vol. 51,pp 2263 2196 Azido-3′-deoxythymidine (BW A509U): An Antiviral Agent that 389−392. http://www.cdc.gov/mmwr/preview/mmwrhtml/ 2264 2197 Inhibits the Infectivity and Cytopathic Effect of Human T-lymphotropic mm5118a1.htm (accessed February 17, 2012). 2265 2198 Virus Type III/lymphadenopathy-associated Virus In vitro. Proc. Natl. (46) Fazal, A. HIV Vaccine Trials Begin in Oxford. Br. Med. J. 2000, 2266 2199 Acad. Sci. U. S. A. 1985, 82, 7096−7100. 321, 591. 2267 2200 (29) Morgan, T. Mainstream Strategy for AIDS Group. The New York (47) Kumar, S. Indian Company Offers Low Cost AIDS Drugs. Lancet 2268 2201 Times, [Online], July 22, 1988. http://www.nytimes.com/1988/07/22/ 2001, 357, 616. 2269 2202 nyregion/mainstream-strategy-for-aids-group.html?pagewanted= (48) McNeil, D. G., Jr. W.H.O. Moves to Make AIDS Drugs More 2270 2203 2&src=pm (accessed February 18, 2012). Accessible to Poor Worldwide. The New York Times, [Online], April 23, 2271 2204 (30) Yarchoan, R.; Mitsuya, H.; Thomas, R. V.; Pluda, J. M.; Hartman, 2002. http://www.nytimes.com/2002/04/23/health/who-moves-to- 2272 2205 N. R.; Perno, C. F.; Marczyk, K. S.; Allain, J. P.; Johns, D. G.; Broder, S. make-aids-drugs-more-accessible-to-poor-worldwide. 2273 ′ ′ 2206 In vivo Activity Against HIV and Favorable Toxicity Profile of 2 ,3 - html?pagewanted=all&src=pm (accessed November 27, 2011). 2274 − 2207 dideoxyinosine. Science 1989, 245, 412 415. (49) Vass, A. Hopes Rise for Patients with Drug Resistant HIV. Br. 2275 2208 (31) Balzarini, J.; Cooney, D. A.; Dalal, M.; Kang, G. J.; Cupp, J. E.; Med. J. 2002, 325, 62. 2276 ′ ′ 2209 DeClercq,E.;Broder,S.;Johns,D.G.2,3-Dideoxycytidine: (50) Green, E. C. In Rethinking AIDS Prevention: Learning from 2277 2210 Regulation of its Metabolism and Anti-retroviral Potency by Natural Successes in Developing Countries; Praeger: Westport, CT, 2003; pp 1− 2278 2211 Pyrimidine Nucleosides and by Inhibitors of Pyrimidine Nucleotide 374. 2279 2212 Synthesis. Mol. Pharmacol. 1987, 32, 798−806. (51) Gottlieb, S. Bush Legislates for $15bn to be Spent on AIDS. Br. 2280 2213 (32) U.S. Food and Drug Administration. HIV/AIDS Historical Time Med. J. 2003, 326, 1233. 2281 2214 Line 1991−1994. http://www.fda.gov/ForConsumers/ByAudience/ (52) Eaton, L. AIDS Vaccine may Offer Hope Only for Some Ethnic 2282 2215 ForPatientAdvocates/HIVandAIDSActivities/ucm151078.htm (ac- Groups. Br. Med. J. 2003, 326, 463. 2283 2216 cessed February 18, 2012). (53) McCarthy, M. HIV Vaccine Fails in Phase 3 Trial. Lancet 2003, 2284 2217 (33) New H.I.V. Strains Resist AIDS Drug. The New York Times, 361, 755−756. 2285 2218 [Online], January 1, 1993. http://partners.nytimes.com/library/ (54) U.S. Food and Drug Administration. Fuzeon (Enfuvirtide) for 2286 2219 national/science/aids/010193sci-aids.html (accessed February 18, Injection. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2287 2220 2012). 2011/021481s020lbl.pdf (accessed November 27, 2011). 2288 2221 (34) Riddler, S. A.; Anderson, R. E.; Mellors, J. W. Antiretroviral (55) Hurwitz, S. J.; Schinazi, R. F. Practical Considerations For 2289 2222 Activity of Stavudine (2′,3′-didehydro-3′-deoxythymidine, d4T). Developing Nucleoside Reverse Transcriptase Inhibitors. Drug 2290 − 2223 Antiviral Res. 1995, 27, 189−203. Discovery Today: Technol. 2012, 9, e183 e193. 2291 2224 (35) Connor, E. M.; Sperling, R. S.; Gelber, R.; Kiselev, P.; Scott, G.; (56) Darque, A.; Valette, G.; Rousseau, F.; Wang, L. H.; Sommadossi, J. 2292 2293 2225 O’Sullivan, M. J.; VanDyke, R.; Bey, M.; Shearer, W.; Jacobson, R. L.; P.; Zhou, X. J. Quantitation of Intracellular Triphosphate of Emtricitabine in Peripheral Blood Mononuclear Cells from Human 2294 2226 Jimenez, E.; O’Neill, E.; Bazin, B.; Delfraissy, J.-F.; Culnane, M.; Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemo- 2295 2227 Coombs, R.; Elkins, M.; Moye, J.; Stratton, P.; Balsley, J. Reduction of ther. 1999, 43, 2245−2250. 2296 2228 Maternal-Infant Transmission of Human Immunodeficiency Virus Type (57) Kapp, C. AIDS Campaign Signals New WHO Priorities and 2297 2229 1 with Zidovudine Treatment. N. Engl. J. Med. 1994, 331, 1173−1180. Approach. Lee Promises to Focus on Real Targets and Improving 2298 2230 (36) Persaud, D.; Gay, H.; Ziemniak, C.; Chen, Y. H.; Piatak, M., Jr.; WHO’s Effectiveness. Lancet 2003, 362, 1900−1901. 2299 2231 Chun, T.-W.; Strain, M.; Richman, D.; Luzuriaga, K. Absence of (58) Wu, Z.; Sullivan, S. G.; Wang, Y.; Rotheram-Borus, M. J.; Detels, 2300 2232 Detectable HIV-1 Viremia after Treatment Cessation in an Infant. N. R. Evolution of China’s Response to HIV/AIDS. Lancet 2007, 369, 2301 2233 Engl. J. Med. 2013, 369, 1828−1835. 679−690. 2302 2234 (37) Szabo, L. HIV Infection Returns in Mississippi Girl Thought (59) Parfitt, T. Global Fund Suspends Payments to Ukraine. Lancet 2303 2235 Cured. USA Today, [Online], July 14, 2014. http://www.usatoday.com/ 2004, 363, 540. 2304 2236 story/news/nation/2014/07/10/baby-hiv-returns-mississippi/ (60) U.S. Department of Health & Human Services. FDA Approves 2305 2237 12480595/ (accessed August 18, 2014). First Oral Fluid Based Rapid HIV Test Kit. http://www.fda.gov/ 2306 2238 (38) U.S. Food and Drug Administration. FDA Announces Possible NewsEvents/Newsroom/PressAnnouncements/2004/ucm108272. 2307 2239 Safety Concern for HIV Drug Combination. http://www.fda.gov/ htm (accessed February 16, 2012). 2308 2240 NewsEvents/Newsroom/PressAnnouncements/2010/ucm201552. (61) U.S. Department of State. Bringing Hope and Saving Lives: 2309 2241 htm (accessed February 16, 2012). Building Sustainable HIV/AIDS Treatment. http://www.state.gov/ 2310 2242 (39) U.S. Food and Drug Administration. Antiretroviral Drugs Used in documents/organization/36287.pdf (accessed November 27, 2011). 2311 2243 the Treatment of HIV Infection. http://www.fda.gov/forpatients/ (62) U.S. Department of Health & Human Services. FDA Grants 2312 2244 illness/hivaids/treatment/ucm118915.htm (accessed March 18, 2013). Tentative Approval to Generic AIDS Drug Regimen for Potential 2313 2245 (40) U.S. Food and Drug Administration. Highlights of Prescribing Purchase Under the President’s Emergency Plan for AIDS Relief. 2314 2246 Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ 2315 2247 2010/020933s022,020636s032lbl.pdf (accessed February 16, 2012). 2005/ucm108407.htm (accessed November 27, 2011). 2316

AM DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2317 (63) Pollack, A. New Medicine for AIDS Is One Pill, Once a Day. The (79) Staples, C. T., Jr.; Rimland, D.; Dudas, D. Hepatitis C in the HIV 2385 2318 New York Times, [Online], July 9, 2006. http://www.nytimes.com/ (Human Immunodeficiency Virus) Atlanta V.A. (Veterans Affairs 2386 2319 2006/07/09/health/09aids.html?pagewanted=1&_r=0 (accessed No- Medical Center) Cohort Study (HAVACS): The Effect of Coinfection 2387 2320 vember 27, 2011). on Survival. Clin. Infect. Dis. 1999, 29, 150−154. 2388 2321 (64) U.S. Department of Health & Human Services. FDA Approves (80) Centers for Disease Control and Prevention. HIV/AIDS and 2389 2322 the First Once-a-Day Three-Drug Combination Tablet for Treatment of Viral Hepatitis. http://www.cdc.gov/hepatitis/Populations/hiv.htm 2390 2323 HIV-1. http://www.fda.gov/NewsEvents/Newsroom/ (accessed April 17, 2012). 2391 2324 PressAnnouncements/2006/ucm108689.htm?utm_campaign= (81) Sulkowski, M. S.; Mast, E. E.; Seeff, L. B.; Thomas, D. L. Hepatitis 2392 2325 Google2&utm_source=fdaSearch&utm_medium=website&utm_ C Virus Infection as an Opportunistic Disease in Persons Infected with 2393 2326 term=2006%20HIV%20pill&utm_content=1 (accessed May 29, 2012). Human Immunodeficiency Virus. Clin. Infect. Dis. 2000, 30, S77−S84. 2394 2327 (65) Tuske, S.; Sarafianos, S. G.; Clark, A. D., Jr.; Ding, J.; Naeger, L. (82) Thomas, D. L.; Villano, S. A.; Riester, K. A.; Hershow, R.; 2395 2328 K.; White, K. L.; Miller, M. D.; Gibbs, C. S.; Boyer, P. L.; Clark, P.; Wang, Mofenson, L. M.; Landesman, S. H.; Hollinger, F. B.; Davenny, K.; Riley, 2396 2329 G.; Gaffney, B. L.; Jones, R. A.; Jerina, D. M.; Hughes, S. H.; Arnold, E. L.; Diaz, C.; Tang, H. B.; Quinn, T. C. Perinatal Transmission of 2397 2330 Structures of HIV-1 RT-DNA Complexes Before and After Incorpo- from Human Immunodeficiency Virus Type 1- 2398 2331 ration of the Anti-AIDS Drug Tenofovir. Nat. Struct. Mol. Biol. 2004, 11, Infected Mothers. J. Infect. Dis. 1998, 177, 1480−1488. 2399 2332 469−474. (83) Woitas, R. P.; Rockstroh, J. K.; Beier, I.; Jung, G.; Kochan, B.; 2400 2333 (66) U.S. Food and Drug Administration. Isentress (Raltegravir) Matz, B.; Brackmann, H. H.; Sauerbruch, T.; Spengler, U. Antigen- 2401 2334 Tablets. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ Specific Cytokine Response to Hepatitis C Virus Core Epitopes in HIV/ 2402 2335 022145s004lbl.pdf (accessed February 16, 2012). Hepatitis C Virus-Coinfected Patients. AIDS 1999, 13, 1313−1322. 2403 2336 (67) U.S. Food and Drug Administration. Selzentry (Maraviroc) (84) Bonnard, P.; Lescure, F. X.; Amiel, C.; Guiard-Schmid, J. B.; 2404 2337 Tablets. http://www.fda.gov/downloads/drugs/drugsafety/ Callard, P.; Gharakhanian, S.; Pialoux, G. Documented Rapid Course of 2405 2338 ucm089122.pdf (accessed February 16, 2012). Hepatic Fibrosis Between Two Biopsies in Patients Coinfected by HIV 2406 2339 (68) Desmon, S. AIDS Vaccine’s Failure Deals Big Blow. The Baltimore and HCV Despite High CD4 Cell Count. J. Viral Hepat. 2007, 14, 806− 2407 2340 Sun, [Online], November 14, 2007. http://articles.baltimoresun.com/ 811. 2408 2341 2007-11-14/news/0711140127_1_vaccine-merck-hiv-infection (ac- (85) McGinnis, K. A.; Fultz, S. L.; Skanderson, M.; Conigliaro, J.; 2409 2342 cessed November 27, 2011). Bryant, K.; Justice, A. C. Hepatocellular Carcinoma and Non-Hodgkin’s 2410 2343 (69) The United States President’s Emergency Plan For AIDS Relief. Lymphoma: The Roles of HIV, Hepatitis C Infection, and Alcohol 2411 2344 PEPFAR: A Commitment Renewal. http://www.pepfar.gov/press/ Abuse. J. Clin. Oncol. 2006, 24, 5005−5009. 2412 2345 107735.htm (accessed November 27, 2011). (86) Cohen, S. D.; Kimmel, P. L. Immune Complex Renal Disease and 2413 2346 (70) Ban congratulates US leader for lifting entry restriction based on Human Immunodeficiency Virus Infection. Semin. Nephrol. 2008, 28, 2414 2347 HIV status. UN News Centre, [Online], October 31, 2009. http://www. 535−544. 2415 2348 un.org/apps/news/story.asp?NewsID=32799&Cr=hiv&Crl=aids#. (87) Szczech, L. A.; Gupta, S. K.; Habash, R.; Guasch, A.; Kalayjian, R.; 2416 2349 VHucSjHF9W4 (accessed February 17, 2012). Appel, R.; Fields, T. A.; Svetkey, L. P.; Flanagan, K. H.; Klotman, P. E.; 2417 2350 (71) Carter, M. US HIV Travel Ban Has Now Ended. Aidsmap, Winston, J. A. The Clinical Epidemiology and Course of the Spectrum of 2418 2351 [Online], January 04, 2010. http://www.aidsmap.com/page/1437294/ Renal Diseases Associated with HIV Infection. Kidney Int. 2004, 66, 2419 2352 (accessed February 17, 2012). 1145−1152. 2420 2353 (72) Abdool Karim, Q.; Abdool Karim, S. S.; Frohlich, J. A.; Grobler, A. (88) Tsui, J.; Vittinghoff, E.; Anastos, K.; Augenbraun, M.; Young, M.; 2421 2354 C.; Baxter, C.; Mansoor, L. E.; Kharsany, A. B. M.; Sibeko, S.; Mlisana, K. Nowicki, M.; Cohen, M. H.; Peters, M. G.; Golub, E. T.; Szczech, L. 2422 2355 P.; Omar, Z.; Gengiah, T. N.; Maarschalk, S.; Arulappan, N.; Mlotshwa, Hepatitis C Seropositivity and Kidney Function Decline Among 2423 2356 M.; Morris, L.; Taylor, D. Effectiveness and Safety of Tenofovir Gel, An Women With HIV: Data From the Women’s Interagency HIV Study. 2424 2357 Antiretroviral Microbicide, for the Prevention of HIV Infection in Am. J. Kidney Dis. 2009, 54,43−50. 2425 2358 Women. Science 2010, 329, 1168−1174. (89) Cheng, J.-T.; Anderson, H. L., Jr.; Markowitz, G. S.; Appel, G. B.; 2426 2359 (73) U.S. Food and Drug Administration. Elvitegravir/Cobicistat/ Pogue, V. A.; D’Agati, V. D. Hepatitis C Virus-Associated Glomerular 2427 2360 Emtricitabine/Tenofovir Disoproxil Fumarate: Antiviral Drugs Advi- Disease in Patients with Human Immunodeficiency Virus Coinfection. J. 2428 2361 sory Committee Meeting Briefing Document. http://www.fda.gov/ Am. Soc. Nephrol. 1999, 10, 1566−1574. 2429 2362 downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ (90) Bruno, R.; Sacchi, P.; Puoti, M.; Soriano, V.; Filice, G. HCV 2430 2363 Drugs/AntiviralDrugsAdvisoryCommittee/UCM303397.pdf (accessed Chronic Hepatitis in Patients with HIV: Clinical Management Issues. 2431 2364 October 15, 2012). Am. J. Gastroenterol. 2002, 97, 1598−1606. 2432 2365 (74) U.S. Food and Drug Administration. TRUVADA (Emtricitabine/ (91) Palmer, S.; Margot, N.; Gilbert, H.; Shaw, N.; Buckheit, R., Jr.; 2433 2366 Tenofovir Disoproxil Fumarate). http://www.fda.gov/downloads/ Miller, M. Tenofovir, Adefovir, and Zidovudine Susceptibilities of 2434 2367 drugs/drugsafety/ Primary Human Immunodeficiency Virus Type 1 Isolates with Non-B 2435 2368 postmarketdrugsafetyinformationforpatientsandproviders/ucm312304. Subtypes or Nucleoside Resistance. AIDS Res. Hum. Retroviruses 2001, 2436 2369 pdf (accessed December 26, 2014). 17, 1167−1173. 2437 2370 (75) U.S. Food and Drug Administration. Elvitegravir/Cobicistat/ (92) De Clercq, E. The Design of Drugs for HIV and HCV. Nat. Rev. 2438 2371 Emtricitabine/Tenofovir Disoproxil Fumarate: Antiviral Drugs Advi- Drug Discovery 2007, 6, 1001−1018. 2439 2372 sory Committee Meeting Briefing Document. http://www.fda.gov/ (93) De Francesco, R.; Migliaccio, G. Challenges and Successes in 2440 2373 downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Developing New Therapies for Hepatitis C. Nature 2005, 436, 953− 2441 2374 Drugs/AntiviralDrugsAdvisoryCommittee/UCM303397.pdf (accessed 960. 2442 2375 October 15, 2012). (94) Carroll, S. S.; Tomassini, J. E.; Bosserman, M.; Getty, K.; Stahlhut, 2443 2376 (76) National Institute of Allergy and Infectious Diseases. Structure of M. W.; Eldrup, A. B.; Bhat, B.; Hall, D.; Simcoe, A. L.; LaFemina, R.; 2444 2377 AIDS. http://www.niaid.nih.gov/topics/HIVAIDS/Understanding/ Rutkowski, C. A.; Wolanski, B.; Yang, Z.; Migliaccio, G.; De Francesco, 2445 2378 Biology/Pages/structure.aspx (accessed February 14, 2012). R.; Kuo, L. C.; MacCoss, M.; Olsen, D. B. Inhibition of Hepatitis C Virus 2446 2379 (77) AIDSinfo. HIV Life Cycle. http://aidsinfo.nih.gov/education- RNA Replication by 2′-Modified Nucleoside Analogs. J. Biol. Chem. 2447 2380 materials/fact-sheets/19/73/the-hiv-life-cycle (accessed November 27, 2003, 278, 11979−11984. 2448 2381 2011). (95) Tomassini, J. E.; Getty, K.; Stahlhut, M. W.; Shim, S.; Bhat, B.; 2449 2382 (78) Barrett, L.; Grant, M. Brothers in Harm: Immunological and Eldrup, A. B.; Prakash, T. P.; Carroll, S. S.; Flores, O.; MacCoss, M.; 2450 2383 Clinical Implications of Coinfection with Hepatitis C Virus and Human McMasters, D. R.; Migliaccio, G.; Olsen, D. B. Inhibitory Effect of 2′- 2451 2384 Immunodeficiency Virus. Clin. Appl. Immunol. Rev. 2002, 2,93−114. Substituted Nucleosides on Hepatitis C Virus Replication Correlates 2452

AN DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2453 with Metabolic Properties in Replicon Cells. Antimicrob. Agents (107) Kowdley, K. V.; Lawitz, E.; Crespo, I.; Hassanein, T.; Davis, M. 2521 2454 Chemother. 2005, 49, 2050−2058. N.; DeMicco, M.; Bernstein, D. E.; Afdhal, N.; Vierling, J. M.; Gordon, S. 2522 2455 (96) De Clercq, E.; Neyts, J. In Antiviral Strategies; Krausslich,̈ H.-G., C.; Anderson, J. K.; Hyland, R. H.; Dvory-Sobol, H.; An, D.; Hindes, R. 2523 2456 Bartenschlager, R., Eds.; Springer Berlin: Heidelberg, 2009; pp 53−84. G.; Albanis, E.; Symonds, W. T.; Berrey, M. M.; Nelson, D. R.; Jacobson, 2524 2457 (97) Olsen, D. B.; Eldrup, A. B.; Bartholomew, L.; Bhat, B.; Bosserman, I. M. Sofosbuvir with Pegylated Interferon Alfa-2a and Ribavirin for 2525 2458 M. R.; Ceccacci, A.; Colwell, L. F.; Fay, J. F.; Flores, O. A.; Getty, K. L.; Treatment-Naive Patients with Hepatitis C Genotype-1 Infection 2526 2459 Grobler, J. A.; LaFemina, R. L.; Markel, E. J.; Migliaccio, G.; Prhavc, M.; (ATOMIC): An Open-Label, Randomised, Multicentre Phase 2 Trial. 2527 2460 Stahlhut, M. W.; Tomassini, J. E.; MacCoss, M.; Hazuda, D. J.; Carroll, S. Lancet 2013, 381, 2100−2107. 2528 2461 S. A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of (108) U.S. Food and Drug Administration. FDA Approves First 2529 2462 Hepatitis C Virus Replication with Excellent Pharmacokinetic Proper- Combination Pills to Treat Hepatitis C. http://www.fda.gov/ 2530 2463 ties. Antimicrob. Agents Chemother. 2004, 48, 3944−3953. newsevents/newsroom/pressannouncements/ucm418365.htm (ac- 2531 2464 (98) Migliaccio, G.; Tomassini, J. E.; Carroll, S. S.; Tomei, L.; cessed December 27, 2014). 2532 2465 Altamura, S.; Bhat, B.; Bartholomew, L.; Bosserman, M. R.; Ceccacci, A.; (109) U.S. Food and Drug Administration. OLYSIO (Simeprevir) 2533 2466 Colwell, L. F.; Cortese, R.; De Francesco, R.; Eldrup, A. B.; Getty, K. L.; Capsules, for Oral Use. http://www.accessdata.fda.gov/drugsatfda_ 2534 2467 Hou, X. S.; LaFemina, R. L.; Ludmerer, S. W.; MacCoss, M.; McMasters, docs/label/2013/205123s001lbl.pdf (accessed December 26, 2014). 2535 2468 D. R.; Stahlhut, M. W.; Olsen, D. B.; Hazuda, D. J.; Flores, O. A. (110) Schinazi, R.; Halfon, P.; Marcellin, P.; Asselah, T. HCV Direct- 2536 2469 Characterization of Resistance to Non-Obligate Chain-Terminating Acting Antiviral Agents: The Best Interferon-Free Combinations. Liver 2537 2470 Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication In Int. 2014, 34,69−78. 2538 2471 Vitro. J. Biol. Chem. 2003, 278, 49164−49170. (111) Pierson, R. FDA Declines to Approve Bristol-Myers Hepatitis 2539 2472 (99) Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Drug. Reuters, [Online], November 26, 2014. http://www.reuters.com/ 2540 2473 Bhat, N.; Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook, article/2014/11/26/us-bristol-myers-hepatitis- 2541 2474 P. D.; Getty, K. L.; MacCoss, M.; McMasters, D. R.; Olsen, D. B.; idUSKCN0JA1QL20141126 (accessed December 27, 2014). 2542 2475 Prakash, T. P.; Prhavc, M.; Song, Q.; Tomassini, J. E.; Xia, J. Structure− (112) U.S. Food and Drug Administration. FDA Approves Viekira Pak 2543 2476 Activity Relationship of Purine Ribonucleosides for Inhibition of to Treat Hepatitis C. http://www.fda.gov/newsevents/newsroom/ 2544 2477 Hepatitis C Virus RNA-Dependent RNA Polymerase. J. Med. Chem. pressannouncements/ucm427530.htm (accessed December 26, 2014). 2545 2478 2004, 47, 2283−2295. (113) Cahn, P.; Villacian, J.; Lazzarin, A.; Katlama, C.; Grinsztejn, B.; 2546 2479 (100) Klumpp, K.; Levéque,̂ V.; Le Pogam, S.; Ma, H.; Jiang, W.-R.; Arasteh, K.; Lopez,́ P.; Clumeck, N.; Gerstoft, J.; Stavrianeas, N.; 2547 2480 Kang, H.; Granycome, C.; Singer, M.; Laxton, C.; Qi Hang, J.; Sarma, K.; Moreno, S.; Antunes, F.; Neubacher, D.; Mayers, D. Ritonavir-Boosted 2548 2481 Smith, D. B.; Heindl, D.; Hobbs, C. J.; Merrett, J. H.; Symons, J.; Tipranavir Demonstrates Superior Efficacy to Ritonavir-Boosted 2549 2482 Cammack, N.; Martin, J. A.; Devos, R.; Najera,́ I. The Novel Nucleoside Protease Inhibitors in Treatment-Experienced HIV-Infected Patients: 2550 2483 Analog R1479 (4′-Azidocytidine) Is a Potent Inhibitor of NS5B- 24-Week Results of the RESIST-2 Trial. Clin. Infect. Dis. 2006, 43, 2551 2484 dependent RNA Synthesis and Hepatitis C Virus Replication in Cell 1347−1356. 2552 2485 Culture. J. Biol. Chem. 2006, 281, 3793−3799. (114) Gathe, J.; Cooper, D. A.; Farthing, C.; Jayaweera, D.; Norris, D.; 2553 2486 (101) Stuyver, L. J.; McBrayer, T. R.; Tharnish, P. M.; Clark, J.; Pierone, G., Jr.; Steinhart, C. R.; Trottier, B.; Walmsley, S. L.; Workman, 2554 2487 Hollecker, L.; Lostia, S.; Nachman, T.; Grier, J.; Bennett, M. A.; Xie, M.- C.; Mukwaya, G.; Kohlbrenner, V.; Dohnanyi, C.; McCallister, S.; 2555 2488 Y.; Schinazi, R. F.; Morrey, J. D.; Julander, J. L.; Furman, P. A.; Otto, M. Mayers, D. Efficacy of the Protease Inhibitors Tipranavir plus Ritonavir 2556 2489 J. Inhibition of Hepatitis C Replicon RNA Synthesis by β-D-2′-deoxy-2′- in Treatment-Experienced Patients: 24-Week Analysis from the 2557 2490 fluoro-2′-C-methylcytidine: A Specific Inhibitor of Hepatitis C Virus RESIST-1 Trial. Clin. Infect. Dis. 2006, 43, 1337−1346. 2558 2491 Replication. Antiviral Chem. Chemother. 2006, 17,79−87. (115) Malcolm, B. A.; Liu, R.; Lahser, F.; Agrawal, S.; Belanger, B.; 2559 2492 (102) Klumpp, K.; Smith, D.; Brandl, M.; Alfredson, T.; Sarma, K.; Butkiewicz, N.; Chase, R.; Gheyas, F.; Hart, A.; Hesk, D.; Ingravallo, P.; 2560 2493 Smith, M.; Najera, I.; Jiang, W.-R.; Le Pogam, S.; Leveque, V.; et al. Jiang, C.; Kong, R.; Lu, J.; Pichardo, J.; Prongay, A.; Skelton, A.; Tong, 2561 2494 Design and Characterization of R1626, A Prodrug of the HCV X.; Venkatraman, S.; Xia, E.; Girijavallabhan, V.; Njoroge, F. G. SCH 2562 2495 Replication Inhibitor R1479 (4′-Azidocytidine) With Enhanced Oral 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 2563 2496 Bioavailability. Antiviral Res. 2007, 74, A35. Protease, Suppresses Polyprotein Maturation and Enhances the 2564 2497 (103) Brandl, M.; Wu, X.; Holper, M.; Hong, L.; Jia, Z.; Birudaraj, R.; Antiviral Activity of Alpha Interferon in Replicon Cells. Antimicrob. 2565 2498 Reddy, M.; Alfredson, T.; Tran, T.; Larrabee, S.; Hadig, X.; Sarma, K.; Agents Chemother. 2006, 50, 1013−1020. 2566 2499 Washington, C.; Hill, G.; Smith, D. B. Physicochemical Properties of the (116) Lin, C.; Lin, K.; Luong, Y.-P.; Rao, B. G.; Wei, Y.-Y.; Brennan, D. 2567 2500 Nucleoside Prodrug R1626 Leading to High Oral Bioavailability. Drug L.; Fulghum, J. R.; Hsiao, H.-M.; Ma, S.; Maxwell, J. P.; Cottrell, K. M.; 2568 2501 Dev. Ind. Pharm. 2008, 34, 683−691. Perni, R. B.; Gates, C. A.; Kwong, A. D. In Vitro Resistance Studies of 2569 2502 (104) Smith, D.; Ma, H.; Le Pogam, S.; Leveque, V.; Brown, C.; Hepatitis C Virus Serine Protease Inhibitors, VX-950 and BILN 2061: 2570 2503 Johansson, N. G.; Kalayanov, G.; Eriksson, S.; Usova, E.; Sund, C.; Structural Analysis Indicates Different Resistant Mechanisms. J. Biol. 2571 2504 Winqist, A.; Maltseva, T.; Smith, M.; Martin, J.; Najera, I.; Klumpp, K. Chem. 2004, 279, 17508−17514. 2572 2505 Novel 4′-Azido-2′-Deoxy-Nucleoside Analogs are Potent Inhibitors of (117) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, 2573 2506 NS5B-Dependent HCV Replication. Antiviral Res. 2007, 74, A36. G.; Bonneau, P.; Bös, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. 2574 2507 (105) Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace,́ L.; 2575 2508 Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; LaPlante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; 2576 2509 Sofia, M. J.; Furman, P. A. Mechanism of Activation of PSI-7851 and Its St. George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, 2577 2510 Diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285, 34337−34347. Y. S.; Weldon, S. M.; Yong, C.-L.; Llinas-Brunet,̀ M. An NS3 Protease 2578 2511 (106) Lawitz, E.; Lalezari, J. P.; Hassanein, T.; Kowdley, K. V.; Inhibitor with Antiviral Effects in Humans Infected with Hepatitis C 2579 2512 Poordad, F. F.; Sheikh, A. M.; Afdhal, N. H.; Bernstein, D. E.; DeJesus, Virus. Nature 2003, 426, 186−189. 2580 2513 E.; Freilich, B.; Nelson, D. R.; Dieterich, D. T.; Jacobson, I. M; Jensen, (118) Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu, 2581 2514 D.; Abrams, G. A.; Darling, J. M.; Rodriguez-Torres, M.; Reddy, K. R.; Y.-T.; Lovey, R. G.; Venkatraman, S.; Pan, W.; Parekh, T.; Pike, R. E.; 2582 2515 Sulkowski, M. S.; Bzowej, N. H.; Hyland, R. H.; Mo, H.; Lin, M.; Mader, Ruan, S.; Liu, R.; Baroudy, B.; Agrawal, S.; Chase, R.; Ingravallo, P.; 2583 2516 M.; Hindes, R.; Albanis, E.; Symonds, W. T.; Berrey, M. M.; Muir, A. Pichardo, J.; Prongay, A.; Brisson, J.-M.; Hsieh, T. Y.; Cheng, K.-C.; 2584 2517 Sofosbuvir in Combination with Peginterferon Alfa-2a and Ribavirin for Kemp, S. J.; Levy, O. E.; Lim-Wilby, M.; Tamura, S. Y.; Saksena, A. K.; 2585 2518 Non-Cirrhotic, Treatment-Naive Patients with Genotypes 1, 2, and 3 Girijavallabhan, V.; Njoroge, F. G. Discovery of SCH446211 (SCH6): A 2586 2519 Hepatitis C Infection: A Randomised, Double-Blind, Phase 2 Trial. New Ketoamide Inhibitor of the HCV NS3 Serine Protease and HCV 2587 2520 Lancet Infect. Dis. 2013, 13, 401−408. Subgenomic RNA Replication. J. Med. Chem. 2006, 49, 2750−2757. 2588

AO DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2589 (119) Jacobson, J. M.; Lalezari, J. P.; Thompson, M. A.; Fichtenbaum, ized, Double-Blind, Placebo-Controlled Dose-Ranging Trial*. HIV Med. 2657 2590 C. J.; Saag, M. S.; Zingman, B. S.; D’Ambrosio, P.; Stambler, N.; 2007, 8, 142−147. 2658 2591 Rotshteyn, Y.; Marozsan, A. J.; Maddon, P. J.; Morris, S. A.; Olson, W. C. (134) Thompson, M. A.; Kessler, H. A.; Eron, J. J., Jr.; Jacobson, J. M.; 2659 2592 Phase 2a Study of the CCR5Monoclonal Antibody PRO 140 Adda, N.; Shen, G.; Zong, J.; Harris, J.; Moxham, C.; Rousseau, F. S. 2660 2593 Administered Intravenously to HIV-Infected Adults. Antimicrob. Agents Short-Term Safety and Pharmacodynamics of Amdoxovir in HIV- 2661 2594 Chemother. 2010, 54, 4137−4142. Infected Patients. AIDS 2005, 19, 1607−1615. 2662 2595 (120) Kuritzkes, D. R.; Jacobson, J.; Powderly, W. G.; Godofsky, E.; (135) Martin, D. E.; Blum, R.; Wilton, J.; Doto, J.; Galbraith, H.; 2663 2596 DeJesus, E.; Haas, F.; Reimann, K. A.; Larson, J. L.; Yarbough, P. O.; Burgess, G. L.; Smith, P. C.; Ballow, C. Safety and Pharmacokinetics of 2664 2597 Curt, V.; Shanahan, W. R., Jr. Antiretroviral Activity of the Anti- Bevirimat (PA-457), A Novel Inhibitor of Human Immunodeficiency 2665 2598 CD4Monoclonal Antibody TNX-355 in Patients Infected with HIV Virus Maturation, in Healthy Volunteers. Antimicrob. Agents Chemother. 2666 − 2599 Type 1. J. Infect. Dis. 2004, 189, 286−291. 2007, 51, 3063 3066. 2667 2600 (121) Nowicka-Sans, B.; Gong, Y.-F.; McAuliffe, B.; Dicker, I.; Ho, H.- (136) Schinazi, R. F.; Massud, I.; Rapp, K. L.; Cristiano, M.; Detorio, 2668 2601 T.; Zhou, N.; Eggers, B.; Lin, P.-F.; Ray, N.; Wind-Rotolo, M.; Zhu, L.; M. A.; Stanton, R. A.; Bennett, M. A.; Kierlin-Duncan, M.; Lennerstrand, 2669 2602 Majumdar, A.; Stock, D.; Lataillade, M.; Hanna, G. J.; Matiskella, J. D.; J.; Nettles, J. H. Selection and Characterization of HIV-1 with a Novel 2670 2603 Ueda, Y.; Wang, T.; Kadow, J. F.; Meanwell, N. A.; Krystal, M. In Vitro S68 Deletion in Reverse Transcriptase. Antimicrob. Agents Chemother. 2671 − 2604 Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, 2011, 55, 2054 2060. 2672 2605 the Active Component of the Prodrug BMS-663068. Antimicrob. Agents (137) Mandell, L. A.; Niederman, M. Antimicrobial Treatment of 2673 2606 Chemother. 2012, 56, 3498−3507. Community Acquired Pneumonia in Adults: A Conference Report. Can. 2674 − 2607 (122) Wilkin, T. J.; Gulick, R. M. CCR5 Antagonism in HIV Infection: J. Infect. Dis. 1993, 4,25 28. 2675 2608 Current Concepts and Future Opportunities. Annu. Rev. Med. 2012, 63, (138) Rello, J.; Pop-Vicas, A. Clinical Review: Primary Viral 2676 − 2609 81−93. Pneumonia. Crit. Care 2009, 13, 235 240. 2677 2610 (123) Shimura, K.; Kodama, E.; Sakagami, Y.; Matsuzaki, Y.; (139) Tang, J. W.; Shetty, N.; Lam, T. T. Y. Principles and Practice of 2678 2679 2611 Watanabe, W.; Yamataka, K.; Watanabe, Y.; Ohata, Y.; Doi, S.; Sato, Infectious Diseases; Mandell, Bennett, Dolin, Eds.; Antimicrobe: − 2680 2612 M.; Kano, M.; Ikeda, S.; Matsuoka, M. Broad Antiretroviral Activity and Pennsylvania, 2000; pp 2060 2085. (140) Gubareva, L. V.; Webster, R. G.; Hayden, F. G. Comparison of 2681 2613 Resistance Profile of the Novel Human Immunodeficiency Virus the Activities of Zanamivir, Oseltamivir, and RWJ-270201 against 2682 2614 Integrase Inhibitor Elvitegravir (JTK-303/GS-9137). J. Virol. 2008, 82, Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor- 2683 2615 764−774. Resistant Variants. Antimicrob. Agents Chemother. 2001, 45, 3403−3408. 2684 2616 (124) Garrido, C.; Soriano, V.; Geretti, A. M.; Zahonero, N.; Garcia, S.; (141) De Clercq, E. Antiviral Drugs in Current Clinical Use. J. Clin. 2685 2617 Booth, C.; Gutierrez, F.; Viciana, I.; de Mendoza, C. Resistance Virol. 2004, 30, 115−133. 2686 2618 Associated Mutations to Dolutegravir (S/GSK1349572) in HIV- (142) U.S. Food and Drug Administration. Influenza (Flu) Antiviral 2687 2619 Infected Patients − Impact of HIV Subtypes and Prior Raltegravir Drugs and Related Information. http://www.fda.gov/drugs/ 2688 2620 Experience. Antiviral Res. 2011, 90, 164−167. drugsafety/informationbydrugclass/ucm100228.htm (accessed May 2689 2621 (125) Papastamopoulos, V.; Skoutelis, A.; Hellenic Center for Disease 25, 2014). 2690 2622 Control & Prevention. HIV treatment: What’s in the Pipeline. (143) Lok, A. S. F.; McMahon, B. J. Chronic Hepatitis B. Hepatology 2691 2623 December 13, 2011. http://www2.keelpno.gr/blog/?p=970&lang=en 2007, 45, 507−539. 2692 2624 (accessed June 15, 2012). (144) Lau, J. Y. N.; Wright, T. L. Molecular Virology and Pathogenesis 2693 2625 (126) Corbau, R.; Mori, J.; Phillips, C.; Fishburn, L.; Martin, A.; of Hepatitis B. Lancet 1993, 342, 1311−1340. 2694 2626 Mowbray, C.; Panton, W.; Smith-Burchnell, C.; Thornberry, A.; (145) Okamoto, H.; Tsuda, F.; Sakugawa, H.; Sastrosoewignjo, R. I.; 2695 2627 Ringrose, H.; Knöchel, T.; Irving, S.; Westby, M.; Wood, A.; Perros, Imai, M.; Miyakawa, Y.; Mayumi, M. Typing Hepatitis B Virus by 2696 2628 M. Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Homology in Nucleotide Sequence: Comparison of Surface Antigen 2697 2629 Activity Against Drug-Resistant Human Immunodeficiency Virus Type Subtypes. J. Gen. Virol. 1988, 69, 2575−2583. 2698 2630 − 1. Antimicrob. Agents Chemother. 2010, 54, 4451 4463. (146) Peters, M. G.; Singer, G.; Howard, T.; Jacobsmeyer, S.; Xiong, 2699 2631 (127) Gupta, K. M.; Pearce, S. M.; Poursaid, A. E.; Aliyar, H. A.; X.; Gibbs, C. S.; Lamy, P.; Murray, A. Fulminant Hepatic Failure 2700 2632 Tresco, P. A.; Mitchnik, M. A.; Kiser, P. F. Polyurethane Intravaginal Resulting from Lamivudine-Resistant Hepatitis B Virus in a Renal 2701 2633 Ring for Controlled Delivery of Dapivirine, A Nonnucleoside Reverse Transplant Recipient: Durable Response After Orthotopic Liver 2702 − 2634 Transcriptase Inhibitor of HIV-1. J. Pharm. Sci. 2008, 97, 4228 4239. Transplantation on Adefovir Dipivoxil and Hepatitis B Immune 2703 2635 (128) Clay, P. G.; McRae, M. P.; Laurent, J.-P. Safety, Tolerability, and Globulin. Transplantation 1999, 68, 1912−1914. 2704 2636 Pharmacokinetics of KP-1461 in Phase I Clinical Studies. J. Int. Assoc. (147) Zoulim, F. Entecavir: A New Treatment Option for Chronic 2705 − 2637 Provid. AIDS Care 2011, 10, 232 238. Hepatitis B. J. Clin. Virol. 2006, 36,8−12. 2706 2638 (129) Holdich, T.; Shiveley, L. A.; Sawyer, J. Pharmacokinetics of (148) U.S. Food and Drug Administration. Baraclude (Entecavir) 2707 2639 Single Oral Doses of Apricitabine, A Novel Deoxycytidine Analogue Tablets. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/ 2708 2640 Reverse Transcriptase Inhibitor, in Healthy Volunteers. Clin. Drug 021797s005,021798s006lbl.pdf (accessed May 26, 2014). 2709 − 2641 Invest. 2006, 26, 279 286. (149) Matthews, S. J. Telbivudine for the Management of Chronic 2710 2642 (130) Colucci, P.; Pottage, J. C.; Robison, H.; Turgeon, J.; Ducharme, Hepatitis B Virus Infection. Clin. Ther. 2007, 29, 2635−2653. 2711 2643 M. P. Effect of a Single Dose of Ritonavir on the Pharmacokinetic (150) U.S. Food and Drug Administration. Tyzeka (Telbivudine) 2712 2644 Behavior of Elvucitabine, A Nucleoside Reverse Transcriptase Inhibitor, Label Revisions. http://www.fda.gov/forpatients/illness/hepatitisbc/ 2713 2645 Administered in Healthy Volunteers. Antimicrob. Agents Chemother. ucm337306.htm (accessed May 27, 2014). 2714 2646 2009, 53, 646−650. (151) U.S. Food and Drug Administration. Changes to VIREAD 2715 2647 (131) Hurwitz, S. J.; Otto, M. J.; Schinazi, R. F. Comparative (Tenofovir DF) Labeling for Hepatitis B. Services. http://www.fda.gov/ 2716 2648 Pharmacokinetics of Racivir,(+/-)-beta-2′,3′-dideoxy-5-fluoro-3′-thia- forpatients/illness/hepatitisbc/ucm362732.htm (accessed May 27, 2717 2649 cytidine in Rats, Rabbits, Dogs, Monkeys and HIV-Infected Humans. 2014). 2718 2650 Antiviral Chem. Chemother. 2005, 16, 117−127. (152) Chong, Y.; Chu, C. K. Understanding the Unique Mechanism of 2719 2651 (132) Herman, B. D.; Sluis-Cremer, N. In Pharmacology; Gallelli, L., L-FMAU (Clevudine) against Hepatitis B Virus: Molecular Dynamics 2720 2652 Ed.; InTech: Rijeka, Croatia, 2012; pp 63−80. Studies. Bioorg. Med. Chem. Lett. 2002, 12, 3459−3462. 2721 2653 (133) Ghosn, J.; Quinson, A.-M.; Sabo, N. D.; Cotte, L.; Piketty, C.; (153) Low, T. L.; Goldstein, A. L. Thymosins: Structure, Function and 2722 2654 Dorleacq,́ N.; Bravo, M.-L.; Mayers, D.; Harmenberg, J.; Mardh,̊ G.; Therapeutic Applications. Thymus 1984, 6,27−42. 2723 2655 Valdez, H.; Katlama, C. Antiviral Activity of Low-Dose Alovudine in (154) zur Hausen, H.; De Villiers, E.-M. Human Papilloma Viruses. 2724 2656 Antiretroviral-Experienced Patients: Results from a 4-week Random- Annu. Rev. Microbiol. 1994, 48, 427−447. 2725

AP DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2726 (155) World Health Organization. Human Papillomavirus Laboratory M.; Upton, C.; Roper, R. L. The Genome Sequence of the SARS- 2794 2727 Manual. http://whqlibdoc.who.int/hq/2010/WHO_IVB_10.12_eng. Associated Coronavirus. Science 2003, 300, 1399−1404. 2795 2728 pdf (accessed June 01, 2014). (172) U.S. Department of Health & Human Services. FDA Efforts to 2796 2729 (156) Centers for Disease Control and Prevention. Human Combat the SARS Outbreak. http://www.fda.gov/newsevents/ 2797 2730 Papillomavirus (HPV) Infection. http://www.cdc.gov/std/treatment/ testimony/ucm161401.htm (accessed May 30, 2014). 2798 2731 2010/hpv.htm (accessed June 01, 2014). (173) Chu, C. M.; Cheng, V. C. C.; Hung, I. F. N.; Wong, M. M. L.; 2799 2732 (157) U.S. Food and Drug Administration. FDA Approves First Chan, K. H.; Chan, K. S.; Kao, R. Y. T.; Poon, L. L. M.; Wong, C. L. P.; 2800 2733 Human Papillomavirus Test for Primary Cervical Cancer Screening. Guan, Y.; Peiris, J. S. M.; Yuen, K. Y. Role of Lopinavir/Ritonavir in the 2801 2734 http://www.fda.gov/newsevents/newsroom/pressannouncements/ Treatment of SARS: Initial Virological and Clinical Findings. Thorax 2802 − 2735 ucm394773.htm (accessed June 01, 2014). 2004, 59, 252 256. 2803 2736 (158) Hall, C. B. In Principles and Practice of Clinical Virology; (174) Glass,R.I.;Parashar,U.D.;Estes,M.K.Norovirus2804 − 2737 Zuckerman, A. J., Banatvala, J. E., Pattison, J. R., Eds.; John Wiley & Gastroenteritis. N. Engl. J. Med. 2009, 361, 1776 1785. 2805 2738 Sons: Chichester, U.K., 1998; pp 293−306. (175) Zheng, D.-P.; Ando, T.; Fankhauser, R. L.; Beard, R. S.; Glass, R. 2806 2739 (159) Mclntosh, K. In Viral Infections of Humans; Evans, A. S., Kaslow, I.; Monroe, S. S. Norovirus Classification and Proposed Strain 2807 − 2740 R. A., Eds.; Springer: New York, 1997; pp 691−711. Nomenclature. Virology 2006, 346, 312 323. 2808 2741 (160) U.S. Food and Drug Administration. Synagis (Palivizumab) for (176) Hardy, M. E. Norovirus Protein Structure and Function. FEMS 2809 − 2742 Intramuscular Administration. http://www.accessdata.fda.gov/ Microbiol. Lett. 2005, 253,1 8. 2810 2743 drugsatfda_docs/label/2008/103770s5113lbl.pdf (accessed June 01, (177) Wobus, C. E.; Karst, S. M.; Thackray, L. B.; Chang, K.-O.; 2811 2744 2014). Sosnovtsev, S. V.; Belliot, G.; Krug, A.; Mackenzie, J. M.; Green, K. Y.; 2812 2745 (161) U.S. Department of Health & Human Services. Palivizumab Virgin, H. W., IV Replication of Norovirus in Cell Culture Reveals a 2813 2746 Product Approval InformationLicensing Action. http://www.fda. Tropism for Dendritic Cells and Macrophages. PLoS Biol. 2004, 2, e432. 2814 2747 gov/drugs/developmentapprovalprocess/ (178) Chang, K.-O.; George, D. W. Interferons and Ribavirin 2815 2748 howdrugsaredevelopedandapproved/approvalapplications/ Effectively Inhibit Norwalk Virus Replication in Replicon-Bearing 2816 − 2817 2749 therapeuticbiologicapplications/ucm093366.htm (accessed June 01, Cells. J. Virol. 2007, 81, 12111 12118. 2818 2750 2014). (179) Binford, S. L.; Maldonado, F.; Brothers, M. A.; Weady, P. T.; Zalman, L. S.; Meador, J. W., III; Matthews, D. A.; Patick, A. K. 2819 2751 (162) Huang, C.-C.; Nguyen, D.; Fernandez, J.; Yun, K. Y.; Fry, K. E.; Conservation of Amino Acids in Human Rhinovirus 3C Protease 2820 2752 Bradley, D. W.; Tam, A. W.; Reyes, G. R. Molecular Cloning and Correlates with Broad-Spectrum Antiviral Activity of Rupintrivir, a 2821 2753 Sequencing of the Mexico Isolate of Hepatitis E Virus (HEV). Virology Novel Human Rhinovirus 3C Protease Inhibitor. Antimicrob. Agents 2822 2754 1992, 191, 550−558. Chemother. 2005, 49, 619−626. 2823 2755 (163) U.S. Food and Drug Administration. Hepatitis E Virus (HEV) (180) Rocha-Pereira, J.; Nascimento, M. S. J.; Ma, Q.; Hilgenfeld, R.; 2824 2756 and Blood Transfusion Safety. http://www.fda.gov/downloads/ Neyts, J.; Jochmans, D. The Enterovirus Protease Inhibitor Rupintrivir 2825 2757 advisorycommittees/committeesmeetingmaterials/ Exerts Cross-Genotypic Anti-Norovirus Activity and Clears Cells from 2826 2758 bloodvaccinesandotherbiologics/bloodproductsadvisorycommittee/ the Norovirus Replicon. Antimicrob. Agents Chemother. 2014, 58, 4675− 2827 2759 ucm319542.pdf (accessed June 02, 2014). 4681. 2828 2760 (164) Panda, S. K.; Thakral, D.; Rehman, S. Hepatitis E Virus. Rev. (181) Rocha-Pereira, J.; Jochmans, D.; Dallmeier, K.; Leyssen, P.; 2829 2761 Med. Virol. 2007, 17, 151−180. Nascimento, M. S. J.; Neyts, J. Favipiravir (T-705) Inhibits in vitro 2830 2762 (165) Gouttenoire, J. Sofosbuvir Inhibits Hepatitis E Virus Replication Norovirus Replication. Biochem. Biophys. Res. Commun. 2012, 424, 777− 2831 2763 in vitro and Results in an Additive Effect when Combined with Ribavirin. 780. 2832 2764 Presented at 50th The International Liver Congress 2015, Vienna, (182) Tarantino, D.; Pezzullo, M.; Mastrangelo, E.; Croci, R.; 2833 2765 Austria, April 22−26, 2015. Rohayem, J.; Robel, I.; Bolognesi, M.; Milani, M. Naphthalene-sulfonate 2834 2766 (166) World Health Organization. Dengue Control. http://www.who. Inhibitors of Human Norovirus RNA-dependent RNA-polymerase. 2835 2767 int/denguecontrol/en/ (accessed May 30, 2014). Antiviral Res. 2014, 102,23−28. 2836 2768 (167) Gubler, D. J.; Clark, G. G. Dengue/Dengue Hemorrhagic Fever: (183) Rocha-Pereira, J.; Jochmans, D.; Debing, Y.; Verbeken, E.; 2837 2769 The Emergence of a Global Health Problem. Emerging Infect. Dis. 1995, Nascimento, M. S. J.; Neyts, J. The Viral Polymerase Inhibitor 2′-C- 2838 2770 1,55−57. Methylcytidine Inhibits Norwalk Virus Replication and Protects against 2839 2771 (168) World Health Organization. Dengue and Severe Dengue. Norovirus-Induced Diarrhea and Mortality in a Mouse Model. J. Virol. 2840 2772 http://www.who.int/mediacentre/factsheets/fs117/en/ (accessed 2013, 87, 11798−11805. 2841 2773 May 30, 2014). (184) Rocha-Pereira, J.; Jochmans, D.; Neyts, J. Prophylactic 2842 2774 (169) Welsch, S.; Miller, S.; Romero-Brey, I.; Merz, A.; Bleck, C. K. E.; Treatment with the Nucleoside Analogue 2′-C-Methylcytidine 2843 2775 Walther, P.; Fuller, S. D.; Antony, C.; Krijnse-Locker, J.; Bartenschlager, Completely Prevents Transmission of Norovirus. J. Antimicrob. 2844 2776 R. Composition and Three-Dimensional Architecture of the Dengue Chemother. 2015, 70, 190. 2845 − 2777 Virus Replication and Assembly Sites. Cell Host Microbe 2009, 5, 365 (185) Gonzalez-Hernandez, M. J.; Pal, A.; Gyan, K. E.; Charbonneau, 2846 2778 375. M.-E.; Showalter, H. D.; Donato, N. J.; O’Riordan, M.; Wobus, C. E. 2847 2779 (170) Fouchier, R. A. M.; Kuiken, T.; Schutten, M.; van Amerongen, Chemical Derivatives of a Small Molecule Deubiquitinase Inhibitor have 2848 2780 G.; van Doornum, G. J. J.; van den Hoogen, B. G.; Peiris, M.; Lim, W.; Antiviral Activity against Several RNA Viruses. PLoS One 2014, 9, 2849 ̈ ’ 2781 Stohr, K.; Osterhaus, A. D. M. E. Aetiology: Koch s Postulates Fulfilled e94491. 2850 2782 for SARS Virus. Nature 2003, 423, 240. (186) Chaudhry, Y.; Nayak, A.; Bordeleau, M.-E.; Tanaka, J.; Pelletier, 2851 2783 (171) Marra, M. A.; Jones, S. J. M.; Astell, C. R.; Holt, R. A.; Brooks- J.; Belsham, G. J.; Roberts, L. O.; Goodfellow, I. G. Caliciviruses Differ in 2852 2784 Wilson, A.; Butterfield, Y. S. N.; Khattra, J.; Asano, J. K.; Barber, S. A.; Their Functional Requirements for eIF4F Components. J. Biol. Chem. 2853 2785 Chan, S. Y.; Cloutier, A.; Coughlin, S. M.; Freeman, D.; Girn, N.; 2006, 281, 25315−25325. 2854 2786 Griffith, O. L.; Leach, S. R.; Mayo, M.; McDonald, H.; Montgomery, S. (187) Lu, G.; Hu, Y.; Wang, Q.; Qi, J.; Gao, F.; Li, Y.; Zhang, Y.; Zhang, 2855 2787 B.; Pandoh, P. K.; Petrescu, A. S.; Robertson, A. G.; Schein, J. E.; W.; Yuan, Y.; Bao, J.; Zhang, B.; Shi, Y.; Yan, J.; Gao, G. F. Molecular 2856 2788 Siddiqui, A.; Smailus, D. E.; Stott, J. M.; Yang, G. S.; Plummer, F.; Basis of Binding Between Novel Human Coronavirus MERS-CoV and 2857 2789 Andonov, A.; Artsob, H.; Bastien, N.; Bernard, K.; Booth, T. F.; its Receptor CD26. Nature 2013, 500, 227−231. 2858 2790 Bowness, D.; Czub, M.; Drebot, M.; Fernando, L.; Flick, R.; Garbutt, M.; (188) Mailles, A.; Blanckaert, K.; Chaud, P.; van der Werf, S.; Lina, B.; 2859 2791 Gray, M.; Grolla, A.; Jones, S.; Feldmann, H.; Meyers, A.; Kabani, A.; Li, Caro, V.; Campese, C.; Guery,́ B.; Prouvost, H.; Lemaire, X.; Paty, M. C.; 2860 2792 Y.; Normand, S.; Stroher, U.; Tipples, G. A.; Tyler, S.; Vogrig, R.; Ward, Haeghebaert, S.; Antoine, D.; Ettahar, N.; Noel, H.; Behillil, S.; 2861 2793 D.; Watson, B.; Brunham, R. C.; Krajden, M.; Petric, M.; Skowronski, D. Hendricx, S.; Manuguerra, J. C.; Enouf, V.; La Ruche, G.; Semaille, C.; 2862

AQ DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

2863 Coignard, B.; Levy-Bruhl,́ D.; Weber, F.; Saura, C.; Che, D. First cases of newsroom/pressannouncements/ucm333233.htm (accessed June 07, 2932 2864 Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 2014). 2933 2865 Infections in France, Investigations and Implications for the Prevention (209) Centers for Disease Control and Prevention. Genital Herpes - 2934 2866 of Human-to-Human Transmission, France, May 2013. Euro Surveill. CDC Fact Sheet. http://www.cdc.gov/std/Herpes/STDFact-Herpes. 2935 2867 2013, 18. htm (accessed June 08, 2014). 2936 2868 (189) de Groot, R. J.; Baker, S. C.; Baric, R. S.; Brown, C. S.; Drosten, (210) Roizman, B. In The herpesviruses; Roizman, B., Ed.; Springer: 2937 2869 C.; Enjuanes, L.; Fouchier, R. A. M.; Galiano, M.; Gorbalenya, A. E.; New York, 1982; pp 1−23. 2938 2870 Memish, Z. A.; Perlman, S.; Poon, L. L. M.; Snijder, E. J.; Stephens, G. (211) World Health Organization. Laboratory Diagnosis of Sexually 2939 2871 M.; Woo, P. C. Y; Zaki, A. M.; Zambon, M.; Ziebuhr, J. Middle East Transmitted Infections, Including Human Immunodeficiency Virus. 2940 2872 Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of http://apps.who.int/iris/bitstream/10665/85343/1/9789241505840_ 2941 − 2873 the Coronavirus Study Group. J. Virol. 2013, 87, 7790 7792. eng.pdf?ua=1 (accessed June 09, 2014). 2942 2874 (190) Lu, L.; Liu, Q.; Du, L.; Jiang, S. Middle East Respiratory (212) Yu, H.; Chen, J.; Xu, X.; Li, Y.; Zhao, H.; Fang, Y.; Li, X.; Zhou, 2943 2875 Syndrome Coronavirus (MERS-CoV): Challenges in Identifying its W.; Wang, W.; Wang, Y. A Systematic Prediction of Multiple Drug- 2944 − 2876 Source and Controlling its Spread. Microbes Infect. 2013, 15, 625 629. Target Interactions from Chemical, Genomic, and Pharmacological 2945 ́ – 2877 (191) Hubalek, Z.; Halouzka, J. West Nile Fever A Reemerging Data. PLoS One 2012, 7, e37608. 2946 ̈ 2878 Mosquito-Borne Viral Disease in Europe. Emerging Infect. Dis. 1999, 5, (213) Sundquist, B.; Oberg, B. Phosphonoformate Inhibits Reverse 2947 − 2879 643 650. Transcriptase. J. Gen. Virol. 1979, 45, 273−281. 2948 2880 (192) U.S. Department of Health & Human Services. Response to the (214) Lawrence, C.; Holmes, K. K. Genital Herpes Simplex Virus 2949 2881 Emerging Threat of West Nile Virus (WNV). http://www.fda.gov/ Infections: Current Concepts in Diagnosis, Therapy and Prevention. 2950 2882 newsevents/testimony/ucm115165.htm (accessed May 31, 2014). Ann. Intern. Med. 1983, 98, 973−983. 2951 2883 (193) Haley, M.; Retter, A. S.; Fowler, D.; Gea-Banacloche, J.; (215) World Health Organization. Ebola Virus Disease. http://www. 2952 ’ 2884 O Grady, N. P. The Role for Intravenous Immunoglobulin in the who.int/csr/don/archive/disease/ebola/en/ (accessed June 09, 2014). 2953 2885 Treatment of West Nile Virus Encephalitis. Clin. Infect. Dis. 2003, 37, (216) World Health Organization. Ebola Virus Disease, West Africa - 2954 − 2886 e88 e90. Update. http://www.who.int/csr/don/2014_06_04_ebola/en/ (ac- 2955 2887 (194) Centers for Disease Control and Prevention. Hepatitis D cessed June 09, 2014). 2956 2888 Information for the Public. http://www.cdc.gov/hepatitis/hdv/index. (217) BBC News Africa, 2014. Ebola: Mapping the Outbreak [Online]. 2957 2889 htm (accessed June 02, 2014). BBC News. Available from: http://www.bbc.com/news/world-africa- 2958 2890 (195) Karayiannis, P. Hepatitis D Virus. Rev. Med. Virol. 1998, 8,13− 28755033 (accessed December 30, 2014). 2959 2891 24. (218) Leroy, E. M.; Kumulungui, B.; Pourrut, X.; Rouquet, P.; 2960 2892 (196) Lavanchy, D. Worldwide Epidemiology of HBV Infection, Hassanin, A.; Yaba, P.; Delicat,́ A.; Paweska, J. T.; Gonzalez, J.-P.; 2961 2893 Disease Burden, and Vaccine Prevention. J. Clin. Virol. 2005, 34,S1−S3. Swanepoel, R. Fruit Bats as Reservoirs of Ebola Virus. Nature 2005, 438, 2962 2894 (197) U.S. Food and Drug Administration. BBB - Hepatitis A Virus. 575−576. 2963 2895 http://www.fda.gov/food/foodborneillnesscontaminants/ (219) PDB ID: 3CSY: Lee, J.E.; Fusco, M.L.; Hessell, A.J.; Oswald, 2964 2896 causesofillnessbadbugbook/ucm071294.htm (accessed June 03, 2014). W.B.; Burton, D.R.; Saphire, E.O. Structure of the Ebola Virus 2965 2897 (198) Alter, M. J.; Mast, E. E. The Epidemiology of Viral Hepatitis in Glycoprotein Bound to an Antibody from a Human Survivor. Nature 2966 2898 the United States. Clin. Gastroenterol. 1994, 23, 437−455. 2008, 454, 177−182. 2967 2899 (199) Parashar, U. D.; Gibson, C. J.; Bresee, J. S.; Glass, R. I. Rotavirus (220) Protein Data Bank. Ebola Virus Proteins. http://www.rcsb.org/ 2968 2900 and Severe Childhood Diarrhea. Emerging Infect. Dis. 2006, 12, 304− pdb/101/motm.do?momID=178 (accessed October 23, 2014). 2969 2901 306. (221) Centers for Disease Control and Prevention. Ebola (Ebola Virus 2970 2902 (200) Crawford, S. E.; Labbe,́ M.; Cohen, J.; Burroughs, M. H.; Zhou, Disease). http://www.cdc.gov/vhf/ebola/treatment/index.html (ac- 2971 2903 Y. J.; Estes, M. K. Characterization of Virus-like Particles Produced by cessed June 09, 2014). 2972 2904 the Expression of Rotavirus Capsid Proteins in Insect Cells. J. Virol. (222) Oestereich, L.; Lüdtke, A.; Wurr, S.; Rieger, T.; Muñoz-Fontela, 2973 2905 1994, 68, 5945−5952. C.; Günther, S. Successful Treatment of Advanced Ebola Virus Infection 2974 2906 (201) U.S. Department of Health & Human Services. Background on with T-705 (Favipiravir) in a Small Animal Model. Antiviral Res. 2014, 2975 2907 Rotavirus. http://www.fda.gov/biologicsbloodvaccines/vaccines/ − 2908 approvedproducts/ucm205542.htm (accessed June 05, 2014). 105,17 21. 2976 2909 (202) Arvin, A. M. Varicella-Zoster Virus. Clin. Microbiol. Rev. 1996, 9, (223) Vo, T.-S.; Kim, S.-K. Potential Anti-HIV Agents from Marine 2977 − 2910 361−381. Resources: An Overview. Mar. Drugs 2010, 8, 2871 2892. 2978 2911 (203) Meier, J. L.; Straus, S. E. Comparative Biology of Latent (224) Aneiros, A.; Garateix, A. Bioactive Peptides from Marine 2979 2912 Varicella-Zoster Virus and Herpes Simplex Virus Infections. J. Infect. Dis. Sources: Pharmacological Properties and Isolation Procedures. J. 2980 − 2913 1992, 166, S13−S23. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2004, 803,41 53. 2981  2914 (204) U.S. Food and Drug Administration. Zostavax (Herpes Zoster (225) Targett, N. M.; Arnold, T. M. Minireview Predicting the 2982 2915 Vaccine) Questions and Answers. http://www.fda.gov/ Effects of Brown Algal Phlorotannins on Marine Herbivores in Tropical 2983 − 2916 biologicsbloodvaccines/vaccines/questionsaboutvaccines/ucm070418. and Temperate Oceans. J. Phycol. 1998, 34, 195 205. 2984 2917 htm (accessed June 07, 2014). (226) Shibata, T.; Kawaguchi, S.; Hama, Y.; Inagaki, M.; Yamaguchi, 2985 2918 (205) Jadhav, A. S.; Pathare, D. B.; Shingare, M. S. Development and K.; Nakamura, T. Local and Chemical Distribution of Phlorotannins in 2986 − 2919 Validation of Enantioselective High Performance Liquid Chromato- Brown Algae. J. Appl. Phycol. 2004, 16, 291 296. 2987 2920 graphic Method for Valacyclovir, an in Drug Substance. J. (227) La Barre, S.; Potin, P.; Leblanc, C.; Delage, L. The Halogenated 2988 2921 Pharm. Biomed. Anal. 2007, 43, 1568−1572. Metabolism of Brown Algae (Phaeophyta), Its Biological Importance 2989 − 2922 (206) dos Santos, D. M.; Canduri, F.; Pereira, J. H.; Vinicius Bertacine and Its Environmental Significance. Mar. Drugs 2010, 8, 988 1010. 2990 2923 Dias, M.; Silva, R. G.; Mendes, M. A.; Palma, M. S.; Basso, L. A.; de (228) Ahn, M. J.; Yoon, K.-D.; Min, S.-Y.; Lee, J. S.; Kim, J. H.; Kim, T. 2991 2924 Azevedo, W. F., Jr.; Santos, D. S. Crystal Structure of Human Purine G.; Kim, S. H.; Kim, N.-G.; Huh, H.; Kim, J. Inhibition of HIV-1 Reverse 2992 2925 Nucleoside Phosphorylase Complexed with Acyclovir. Biochem. Biophys. Transcriptase and Protease by Phlorotannins from the Brown Alga 2993 2926 Res. Commun. 2003, 308, 553−559. Ecklonia cava. Biol. Pharm. Bull. 2004, 27, 544−547. 2994 2927 (207) Nesalin, J. A. J.; Babu, C. J. G.; Kumar, G. V.; Mani, T. T. (229) Lü, L.; Liu, S.-W.; Jiang, S.-B.; Wu, S.-G. Tannin Inhibits HIV-1 2995 2928 Validated Spectrophotometric Estimation of Famciclovir in Tablet Entry by Targeting gp41. Acta Pharmacol. Sin. 2004, 25, 213−218. 2996 2929 Dosage Form. J. Chem. 2009, 6, 780−784. (230) Cai, L.; Jiang, S. Development of Peptide and Small-Molecule 2997 2930 (208) U.S. Food and Drug Administration. FDA Approves Varizig for HIV-1 Fusion Inhibitors that Target gp41. ChemMedChem 2010, 5, 2998 2931 Reducing Chickenpox Symptoms. http://www.fda.gov/newsevents/ 1813−1824. 2999

AR DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3000 (231) Artan, M.; Li, Y.; Karadeniz, F.; Lee, S.-H.; Kim, M.-M.; Kim, S.- Polyphenols) from the Marine Alga Fucus vesiculosus. J. Nat. Prod. 3069 3001 K. Anti-HIV-1 Activity of Phloroglucinol Derivative, 6,6′-bieckol, from 1993, 56, 478−488. 3070 3002 Ecklonia cava. Bioorg. Med. Chem. 2008, 16, 7921−7926. (251) Queiroz, K. C. S.; Medeiros, V. P.; Queiroz, L. S.; Abreu, L. R. D.; 3071 3003 (232) Ahn, M.-J.; Yoon, K.-D.; Kim, C.Y.; Kim, J.H.; Shin, C.-G.; Kim, Rocha, H. A. O.; Ferreira, C. V.; Juca,́ M. B.; Aoyama, H.; Leite, E. L. 3072 3004 J. Inhibitory Activity on HIV-1 Reverse Transcriptase and Integrase of a Inhibition of Reverse Transcriptase Activity of HIV by Polysaccharides 3073 3005 Carmalol Derivative from a Brown Alga. Phytother. Res. 2006, 20, 711− of Brown Algae. Biomed. Pharmacother. 2008, 62, 303−307. 3074 3006 713. (252) Trinchero, J.; Ponce, N. M. A.; Cordoba,́ O. L.; Flores, M. L.; 3075 3007 (233) Nakane, H.; Arisawa, M.; Fujita, A.; Koshimura, S.; Ono, K. Pampuro, S.; Stortz, C. A.; Salomon,́ H.; Turk, G. Antiretroviral Activity 3076 3008 Inhibition of HIV-Reverse Transcriptase Activity by Some Phloroglu- of Fucoidans Extracted from the Brown Seaweed Adenocystis utricularis. 3077 3009 cinol Derivatives. FEBS Lett. 1991, 286,83−85. Phytother. Res. 2009, 23, 707−712. 3078 3010 (234) Ngo, D.-N.; Kim, M.-M.; Kim, S.-K. Chitin Oligosaccharides (253) Lee, J.-B.; Hayashi, K.; Hirata, M.; Kuroda, E.; Suzuki, E.; Kubo, 3079 3011 Inhibit Oxidative Stress in Live Cells. Carbohydr. Polym. 2008, 74, 228− Y.; Hayashi, T. Antiviral Sulfated Polysaccharide from Navicula directa,a 3080 3012 234. Diatom Collected from Deep-Sea Water in Toyama Bay. Biol. Pharm. 3081 3013 (235) Shahidi, F.; Arachchi, J. K. V.; Jeon, Y.-J. Food Applications of Bull. 2006, 29, 2135−2139. 3082 3014 Chitin and Chitosans. Trends Food Sci. Technol. 1999, 10,37−51. (254) Amornrut, C.; Toida, T.; Imanari, T.; Woo, E.-R.; Park, H.; 3083 3015 (236) Sosa, M. A. G.; Fazely, F.; Koch, J. A.; Vercellotti, S. V.; Ruprecht, Linhardt, R.; Wu, S. J.; Kim, Y. S. A New Sulfated β-galactan from Clams 3084 3016 R. M. Carboxymethylchitosan-N,O-sulfate as an Anti-HIV-1 Agent. with Anti-HIV Activity. Carbohydr. Res. 1999, 321, 121−127. 3085 3017 Biochem. Biophys. Res. Commun. 1991, 174, 489−496. (255) Wang, W.; Wang, S.-X.; Guan, H.-S. The Antiviral Activities and 3086 3018 (237) Nishimura, S.-I.; Kai, H.; Shinada, K.; Yoshida, T.; Tokura, S.; Mechanisms of Marine Polysaccharides. Mar. Drugs 2012, 10, 2795− 3087 3019 Kurita, K.; Nakashima, H.; Yamamoto, N.; Uryu, T. Regioselective 2816. 3088 3020 Syntheses of Sulfated Polysaccharides: Specific Anti-HIV-1 Activity of (256) Witvrouw, M.; Este, J. A.; Mateu, M. Q.; Reymen, D.; Andrei, G.; 3089 3021 Novel Chitin Sulfates. Carbohydr. Res. 1998, 306, 427−433. Snoeck, R.; Ikeda, S.; Pauwels, R.; Bianchini, N. V.; Desmyter, J.; De 3090 3022 (238) Artan, M.; Karadeniz, F.; Karagozlu, M.Z.; Kim, M.-M.; Kim, S.- Clercq, E. Activity of a Sulfated Polysaccharide Extracted from the Red 3091 3023 K. Anti-HIV-1 Activity of Low Molecular Weight Sulfated Chitooligo- Seaweed Aghardhiella tenera against Human Immunodeficiency Virus 3092 3024 saccharides. Carbohydr. Res. 2010, 345, 656−662. and Other Enveloped Viruses. Antiviral Chem. Chemother. 1994, 5, 297− 3093 3025 (239) Kim, S.-K.; Rajapakse, N. Enzymatic Production and Biological 303. 3094 3026 Activities of Chitosan Oligosaccharides (COS): A Review. Carbohydr. (257) Yamada, T.; Ogamo, A.; Saito, T.; Uchiyama, H.; Nakagawa, Y. 3095 3027 Polym. 2005, 62, 357−368. Preparation of O-acylated Low-Molecular-Weight Carrageenans with 3096 3028 (240) Park, P.-J.; Je, J.-Y.; Jung, W.-K.; Ahn, C.-B.; Kim, S.-K. Potent Anti-HIV Activity and Low Anticoagulant Effect. Carbohydr. 3097 3029 Anticoagulant Activity of Heterochitosans and Their Oligosaccharide Polym. 2000, 41, 115−120. 3098 3030 Sulfates. Eur. Food Res. Technol. 2004, 219, 529−533. (258) Yamada, T.; Ogamo, A.; Saito, T.; Watanabe, J.; Uchiyama, H.; 3099 3031 (241) Vijayavel, K.; Anbuselvam, C.; Balasubramanian, M. P. Free Nakagawa, Y. Preparation and Anti-HIV Activity of Low-Molecular- 3100 3032 Radical Scavenging Activity of the Marine Mangrove Rhizophora Weight Carrageenans and Their Sulfated Derivatives. Carbohydr. Polym. 3101 3033 apiculata Bark Extract with Reference to Naphthalene Induced 1997, 32,51−55. 3102 3034 Mitochondrial Dysfunction. Chem.-Biol. Interact. 2006, 163, 170−175. (259) Hayashi, T.; Hayashi, K.; Maeda, M.; Kojima, I. Calcium 3103 3035 (242) Alban, S.; Franz, G. Partial Synthetic Glucan Sulfates as Potential Spirulan, an Inhibitor of Enveloped Virus Replication, from a Blue- 3104 3036 New Antithrombotics: A Review. Biomacromolecules 2001, 2, 354−361. Green Alga Spirulina platensis. J. Nat. Prod. 1996, 59,83−87. 3105 3037 (243) Parish, C. R.; Low, L.; Warren, H. S.; Cunningham, A. L. A (260) Xianliang, X.; Meiyu, G.; Huashi, G.; Zelin, L. Effects of Marine 3106 3038 Polyanion Binding Site on the CD4 Molecule. Proximity to the HIV- Polysaccharide 911 on HIV-1 Proliferation In Vitro. Chin. J. Mar. Drugs 3107 3039 gp120 Binding Region. J. Immunol. 1990, 145, 1188−1195. 2000, 19,8−11. 3108 3040 (244) Lynch, G.; Low, L.; Li, S.; Sloane, A.; Adams, S.; Parish, C.; (261) Xianliang, X.; Hua, D.; Meiyu, G.; Pingfang, L.; Yingxia, L.; 3109 3041 Kemp, B.; Cunningham, A. L. Sulfated Polyanions Prevent HIV Huashi, G. Studies of the Anti-AIDS Effects of Marine Polysaccharide 3110 3042 Infection of Lymphocytes by Disruption of the CD4-gp120 Interaction, Drug 911 and its Related Mechanisms of Action. Chin. J. Mar. Drugs 3111 3043 but do not Inhibit Monocyte Infection. J. Leukoc. Biol. 1994, 56, 266− 2000, 19,4−8. 3112 3044 272. (262) Woo, E.-R.; Kim, W. S.; Kim, Y. S. Virus-cell Fusion Inhibitory 3113 3045 (245) Witvrouw, M.; De Clercq, E. Sulfated Polysaccharides Extracted Activity for the Polysaccharides from Various Korean Edible Clams. 3114 3046 from Sea Algae as Potential Antiviral Drugs. Gen. Pharmacol. 1997, 29, Arch. Pharmacal Res. 2001, 24, 514−517. 3115 3047 497−511. (263) Sato, T.; Hori, K. Cloning, Expression, and Characterization of a 3116 3048 (246) Adhikari, U.; Mateu, C. G.; Chattopadhyay, K.; Pujol, C. A.; Novel Anti-HIV Lectin from the Cultured Cyanobacterium. Fish. Sci. 3117 3049 Damonte, E. B.; Ray, B. Structure and Antiviral Activity of Sulfated 2009, 75, 743−753. 3118 3050 Fucans from Stoechospermum marginatum. Phytochemistry 2006, 67, (264) Lifson, J.; Coutre,́ S.; Huang, E.; Engleman, E. Role of Envelope 3119 3051 2474−2482. Glycoprotein Carbohydrate in Human Immunodeficiency Virus (HIV) 3120 3052 (247) Bourgougnon, N.; Lahaye, M.; Quemener, B.; Chermann, J.-C.; Infectivity and Virus-Induced Cell Fusion. J. Exp. Med. 1986, 164, 3121 3053 Rimbert, M.; Cormaci, M.; Furnari, G.; Kornprobst, J.-M. Annual 2101−2106. 3122 3054 Variation in Composition and In Vitro Anti-HIV-1 Activity of the (265) Hansen, J.-E. S.; Nielsen, C.; Heegaard, P.; Mathiesen, L. R.; 3123 3055 Sulfated Glucuronogalactan from Schizymenia dubyi (Rhodophyta, Nielsen, J. O. Correlation Between Carbohydrate Structures on the 3124 3056 Gigartinales). J. Appl. Phycol. 1996, 8, 155−161. Envelope Glycoprotein gp120 of HIV-1 and HIV-2 and Syncytium 3125 3057 (248) Nakashima, H.; Kido, Y.; Kobayashi, N.; Motoki, Y.; Neushul, Inhibition with Lectins. AIDS 1989, 3, 635−642. 3126 3058 M.; Yamamoto, N. Purification and Characterization of an Avian (266) Balzarini, J.; Neyts, J.; Schols, D.; Hosoya, M.; Van Damme, E.; 3127 3059 Myeloblastosis and Human Immunodeficiency Virus Reverse Tran- Peumans, W.; De Clercq, E. The Mannose-specific Plant Lectins from 3128 3060 scriptase Inhibitor, Sulfated Polysaccharides Extracted from Sea Algae. Cymbidium Hybrid and Epipactis helleborine and the (N-acetylglucosa- 3129 − 3061 Antimicrob. Agents Chemother. 1987, 31, 1524 1528. mine)n -specific Plant Lectin from Urtica dioica are Potent and Selective 3130 3062 (249) Nakashima, H.; Kido, Y.; Kobayashi, N.; Motoki, Y.; Neushul, Inhibitors of Human Immunodeficiency Virus and Cytomegalovirus 3131 3063 M.; Yamamoto, N. Antiretroviral Activity in a Marine Red Alga: Reverse Replication In Vitro. Antiviral Res. 1992, 18, 191−207. 3132 3064 Transcriptase Inhibition by an Aqueous Extract of Schizymenia pacifica. (267) Mori, T.; O’Keefe, B. R.; Sowder, R. C., II; Bringans, S.; Gardella, 3133 3065 J. Cancer Res. Clin. Oncol. 1987, 113, 413−416. R.; Berg, S.; Cochran, P.; Turpin, J. A.; Buckheit, R. W., Jr.; McMahon, J. 3134 3066 (250) Beress,́ A.; Wassermann, O.; Bruhn, T.; Beress,́ L.; Kraiselburd, B.; Boyd, M. R. Isolation and Characterization of Griffithsin, a Novel 3135 3067 E. N.; Gonzalez, L. V.; de Motta, G. E.; Chavez, P. I. A New Procedure HIV-inactivating Protein, from the Red Alga Griffithsia sp. J. Biol. Chem. 3136 3068 for the Isolation of Anti-HIV Compounds (Polysaccharides and 2005, 280, 9345−9353. 3137

AS DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3138 (268) Wang, J. H.; Kong, J.; Li, W.; Molchanova, V.; Chikalovets, I.; (285) Loya, S.; Hizi, A. The Inhibition of Human Immunodeficiency 3207 3139 Belogortseva, N.; Luk’yanov, P.; Zheng, Y. T. A Beta-galactose-specific Virus Type 1 Reverse Transcriptase by Avarol and Avarone Derivatives. 3208 3140 Lectin Isolated from the Marine Worm Chaetopterus variopedatus FEBS Lett. 1990, 269, 131−134. 3209 3141 Possesses Anti-HIV-1 Activity. Comp. Biochem. Physiol., Part C: Toxicol. (286) Gul, W.; Hammond, N. L.; Yousaf, M.; Peng, J.; Holley, A.; 3210 3142 Pharmacol. 2006, 142, 111−117. Hamann, M. T. Chemical Transformation and Biological Studies of 3211 3143 (269) Luk’yanov, P. A.; Chernikov, O. V.; Kobelev, S. S.; Chikalovets, I. Marine Sesquiterpene (S)-(+)-Curcuphenol and its Analogs. Biochim. 3212 3144 V.; Molchanova, V. I.; Li, W. Carbohydrate-binding Proteins of Marine Biophys. Acta, Gen. Subj. 2007, 1770, 1513−1519. 3213 3145 Invertebrates. Russ. J. Bioorg. Chem. 2007, 33, 161−169. (287) Althaus, I. W.; Reusser, F.; Tarpley, W. G.; Skaletzky, L. L. 3214 3146 (270) Lee, T.-G.; Maruyama, S. Isolation of HIV-1 Protease-Inhibiting Preparation of Phenanthrolinedicarboxylate Esters, 4-Aminoquinoline 3215 3147 Peptides from Thermolysin Hydrolysate of Oyster Proteins. Biochem. and Isoquinoline Derivatives as Inhibitors of HIV Reverse Tran- 3216 − 3148 Biophys. Res. Commun. 1998, 253, 604 608. scriptase. International Patent WO9005523A2, May 31, 1990. 3217 3149 (271) Boyd, M. R.; Gustafson, K. R.; McMahon, J. B.; Shoemaker, R. (288) Inaba, T.; Yamada, Y.; Shanley, J.; Deason, M. Process for 3218 ’ 3150 H.; O Keefe, B. R.; Mori, T.; Gulakowski, R. J.; Wu, L.; Rivera, M. I.; Producing Amide Derivatives as HIV Protease Inhibitors. International 3219 3151 Laurencot, C. M.; Currens, M. J.; Cardellina, J. H., 2nd; Buckheit, R. W., Patent WO9711938A1, April 3, 1997. 3220 3152 Jr.; Nara, P. L.; Pannell, L. K.; Sowder, R. C., 2nd; Henderson, L. E. (289) Kawano, Y.; Fujii, N.; Kanzaki, N.; Iizawa, Y. Preparation of 3221 3153 Discovery of Cyanovirin-N, a Novel Human Immunodeficiency Virus- Furo[2,3-h]isoquinoline Derivatives as Viral Entry Inhibitors against 3222 3154 Inactivating Protein that Binds Viral Surface Envelope Glycoprotein HIV. International Patent WO03035650A1, May 1, 2003. 3223 3155 gp120: Potential Applications to Microbicide Development. Antimicrob. (290) Kadow, J. F.; Xue, Q. M.; Wang, T.; Zhang, Z.; Meanwell, N. A. 3224 − 3156 Agents Chemother. 1997, 41, 1521 1530. Preparation of Indole, Azaindole and Related Heterocyclic Pyrrolidine 3225 3157 (272) Miyata, T.; Tokunaga, F.; Yoneya, T.; Yoshikawa, K.; Iwanaga, Derivatives as Antiviral Agents. International Patent WO068221A1, 3226 3158 S.; Niwa, M.; Takao, T.; Shimonishi, Y. Antimicrobial Peptides, Isolated August 21, 2003. 3227 3159 from Horseshoe Crab Hemocytes, Tachyplesin II, and Polyphemusins I (291) Romero, D. L.; Morge, R. A.; Genin, M. J.; Biles, C.; Busso, M.; 3228 3160 and II: Chemical Structures and Biological Activity. J. Biochem. 1989, Resnick, L.; Althaus, I. W.; Reusser, F.; Thomas, R. C.; Tarpley, W. G. 3229 − 3161 106, 663 668. Bis (heteroaryl) Piperazine (BHAP) Reverse Transcriptase Inhibitors: 3230 3162 (273) Morimoto, M.; Mori, H.; Otake, T.; Ueba, N.; Kunita, N.; Niwa, Structure-Activity Relationships of Novel Substituted Indole Analogs 3231 3163 M.; Murakami, T.; Iwanaga, S. Inhibitory Effect of Tachyplesin I on the and the Identification of 1-[(5-methanesulfonamido-1H-indol-2-yl) 3232 3164 Proliferation of Human Immunodeficiency Virus In Vitro. Chemo- carbonyl]-4-[3-[(1-methylethyl) amino] pyridinyl] piperazinemono- 3233 3165 therapy 1991, 37, 206−211. methanesulfonate (U-90152S), a Second-Generation Clinical Candi- 3234 3166 (274) Gustafson, K.; Roman, M.; Fenical, W. The Macrolactins, a date. J. Med. Chem. 1993, 36, 1505−1508. 3235 3167 Novel Class of Antiviral and Cytotoxic Macrolides from a Deep-Sea (292) Ford, P. W.; Gustafson, K. R.; McKee, T. C.; Shigematsu, N.; 3236 3168 Marine Bacterium. J. Am. Chem. Soc. 1989, 111, 7519−7524. Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; de Silva, E. D.; Lassota, P.; 3237 3169 (275) Pereira, H. S.; Leao-Ferreira,̃ L. R.; Moussatche,́ N.; Teixeira, V. Allen, T. M.; Van Soest, R.; Andersen, R. J.; Boyd, M. R. Papuamides A- 3238 3170 L.; Cavalcanti, D. N.; Costa, L. J.; Diaz, R.; Frugulhetti, I. C. P. P. D, HIV-Inhibitory and Cytotoxic Depsipeptides from the Sponges 3239 3171 Antiviral Activity of Diterpenes Isolated from the Brazilian Marine Alga Theonella mirabilis and Theonella swinhoei Collected in Papua New 3240 3172 Dictyota menstrualis Against Human Immunodeficiency Virus Type 1 Guinea. J. Am. Chem. Soc. 1999, 121, 5899−5909. 3241 3173 (HIV-1). Antiviral Res. 2004, 64,69−76. (293) Xie, W.; Ding, D.; Zi, W.; Li, G.; Ma, D. Total Synthesis and 3242 3174 (276) Singh, S. B.; Zink, D. L.; Goetz, M. A.; Dombrowski, A. W.; Structure Assignment of Papuamide B, a Potent Marine Cyclo- 3243 3175 Polishook, J. D.; Hazuda, D. J. Equisetin and a Novel Opposite depsipeptide with Anti-HIV Properties. Angew. Chem., Int. Ed. 2008, 3244 3176 Stereochemical Homolog Phomasetin, Two Fungal Metabolites as 47, 2844−2848. 3245 3177 Inhibitors of HIV-1 Integrase. Tetrahedron Lett. 1998, 39, 2243−2246. (294) Andjelic, C. D.; Planelles, V.; Barrows, L. R. Characterizing the 3246 3178 (277) Rowley, D. C.; Hansen, M. S. T.; Rhodes, D.; Sotriffer, C. A.; Ni, Anti-HIV Activity of Papuamide A. Mar. Drugs 2008, 6, 528−549. 3247 3179 H.; McCammon, J. A.; Bushman, F. D.; Fenical, W. Thalassiolins A-C: (295) Zampella, A.; D’Auria, M. V.; Paloma, L. G.; Casapullo, A.; 3248 3180 New Marine-Derived Inhibitors of HIV cDNA Integrase. Bioorg. Med. Minale, L.; Debitus, C.; Henin, Y. Callipeltin A, an Anti-HIV Cyclic 3249 3181 Chem. 2002, 10, 3619−3625. Depsipeptide from the New Caledonian Lithistida Sponge Callipelta sp. 3250 3182 (278) Potts, B. C. M.; Faulkner, D. J.; Chan, J. A.; Simolike, G. C.; − 3183 Offen, P.; Hemling, M. E.; Francis, T. A. Didemnaketals A and B, HIV-1 J. Am. Chem. Soc. 1996, 118, 6202 6209. 3251 3184 Protease Inhibitors from the Ascidian Didemnum sp. J. Am. Chem. Soc. (296) Oku, N.; Gustafson, K. R.; Cartner, L. K.; Wilson, J. A.; 3252 3185 1991, 113, 6321−6322. Shigematsu, N.; Hess, S.; Pannell, L. K.; Boyd, M. R.; McMahon, J. B. 3253 3186 (279) Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J. Neamphamide A, a New HIV-Inhibitory Depsipeptide from the Papua 3254 3187 Cyclodidemniserinol Trisulfate, a Sulfated Serinolipid from the Palauan New Guinea Marine Sponge Neamphius huxleyi. J. Nat. Prod. 2004, 67, 3255 − 3188 Ascidian Didemnum guttatum that Inhibits HIV-1 Integrase. Org. Lett. 1407 1411. 3256 3189 2000, 2, 1605−1607. (297) Plaza, A.; Gustchina, E.; Baker, H. L.; Kelly, M.; Bewley, C. A. 3257 3190 (280) Andersen, R. J.; Faulkner, D. J.; He, C. H.; Van Duyne, G. D.; Mirabamides A-D, Depsipeptides from the sponge Siliquariaspongia 3258 − 3191 Clardy, J. Metabolites of the Marine Prosobranch Mollusk Lamellaria sp. mirabilis That Inhibit HIV-1 Fusion. J. Nat. Prod. 2007, 70, 1753 1760. 3259 3192 J. Am. Chem. Soc. 1985, 107, 5492−5495. (298) Plaza, A.; Bifulco, G.; Keffer, J. L.; Lloyd, J. R.; Baker, H. L.; 3260 3193 (281) Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Bewley, C. A. Celebesides A-C and Theopapuamides B-D, Depsipep- 3261 3194 Rubins, K.; Bushman, F. D.; Venkateswarlu, Y.; Faulkner, D. J. tides from an Indonesian Sponge that Inhibit HIV-Entry. J. Org. Chem. 3262 − 3195 Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against 2009, 74, 504 512. 3263 3196 HIV-1 Virus in Cell Culture. J. Med. Chem. 1999, 42, 1901−1907. (299) Rashid, M. A.; Gustafson, K. R.; Cartner, L. K.; Shigematsu, N.; 3264 3197 (282) Sagar, S.; Kaur, M.; Minneman, K. P. Antiviral Lead Compounds Pannell, L. K.; Boyd, M. R. Microspinosamide, a New HIV-inhibitory 3265 3198 from Marine Sponges. Mar. Drugs 2010, 8, 2619−2638. Cyclic Depsipeptide from the Marine Sponge Sidonops microspinosa. J. 3266 3199 (283) Sarin, P. S.; Sun, D.; Thornton, A.; Müller, W. E. G. Inhibition of Nat. Prod. 2001, 64, 117−121. 3267 3200 Replication of the Etiologic Agent of Acquired Immune Deficiency (300) Zampella, A.; Sepe, V.; Luciano, P.; Bellotta, F.; Monti, M. C.; 3268 3201 Syndrome (Human T-lymphotropic Retrovirus/Lymphadenopathy- D’Auria, M. V.; Jepsen, T.; Petek, S.; Adeline, M.-T.; Laprevó̂te, O.; 3269 3202 associated Virus) by Avarol and Avarone. J. Natl. Cancer Inst. 1987, 78, Aubertin, A.-M.; Debitus, C.; Poupat, C.; Ahond, A. Homophymine A, 3270 3203 663−666. an Anti-HIV Cyclodepsipeptide from the Sponge Homophymia sp. J. 3271 3204 (284) Minale, L.; Riccio, R.; Sodano, G. Avarol, a Novel Org. Chem. 2008, 73, 5319−5327. 3272 3205 Sesquiterpenoid Hydroquinone with a Rearranged Drimane Skeleton (301) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez- 3273 3206 from the Sponge. Tetrahedron Lett. 1974, 15, 3401−3404. Paloma, L.; Riccio, R. Dragmacidin F: A New Antiviral Bromoindole 3274

AT DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3275 Alkaloid from the Mediterranean Sponge Halicortex sp. Tetrahedron (319) Wu, S.-M.; Xu, W.-M.; Xu, Z. Antiviral Effect of Oyster Extract 3344 3276 2000, 56, 3743−3748. Compound Capsule in Ducks Infected by DHBV. Chin. Pharm. J. 1996, 3345 3277 (302) Rey, F.; Barre-Sinoussi,́ F.; Schmidtmayerova, H.; Chermann, J.- 31, 304−307. 3346 3278 C. Detection and Titration of Neutralizing Antibodies to HIV Using an (320) Guan, H. S. Polymeric Mannuronic Acid Sulfate for Treatment 3347 3279 Inhibition of the Cytopathic Effect of the Virus on MT4 Cells. J. Virol. of Hepatitis B. CN1132209A, October 2, 1996. 3348 3280 Methods 1987, 16, 239−249. (321) Na, M.; Ding, Y.; Wang, B.; Tekwani, B. L.; Schinazi, R. F.; 3349 3281 (303) Rey, F.; Dower, G.; Hirsch, I.; Chermann, J.-C. Productive Franzblau, S.; Kelly, M.; Stone, R.; Li, X.-C.; Ferreira, D.; Hamann, M. T. 3350 3282 Infection of CD4+ Cells by Selected HIV Strains is not Inhibited by Anti- Anti-infective Discorhabdins from a Deep-Water Alaskan Sponge of the 3351 3283 CD4Monoclonal Antibodies. Virology 1991, 181, 165−171. Genus Latrunculia. J. Nat. Prod. 2010, 73, 383−387. 3352 3284 (304) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. Manzamine (322) Abbas, S.; Kelly, M.; Bowling, J.; Sims, J.; Waters, A.; Hamann, 3353 3285 A, a Novel Antitumor Alkaloid from a Sponge. J. Am. Chem. Soc. 1986, M. T. Advancement into the Arctic Region for Bioactive Sponge 3354 3286 108, 6404−6405. Secondary Metabolites. Mar. Drugs 2011, 9, 2423−2437. 3355 3287 (305) Edrada, R. A.; Proksch, P.; Wray, V.; Witte, L.; Müller, W. E. G.; (323) Campo, V. L.; Kawano, D. F.; da Silva, D. B., Jr.; Carvalho, I. 3356 3288 Van Soest, R. W. M. Four New Bioactive Manzamine-Type Alkaloids Carrageenans: Biological Properties, Chemical Modifications and 3357 3289 from the Philippine Marine Sponge Xestospongia ashmorica. J. Nat. Prod. Structural Analysis - A Review. Carbohydr. Polym. 2009, 77, 167−180. 3358 3290 1996, 59, 1056−1060. (324) Buck, C. B.; Thompson, C. D.; Roberts, J. N.; Müller, M.; Lowy, 3359 3291 (306) Yousaf, M.; Hammond, N. L.; Peng, J.; Wahyuono, S.; McIntosh, D. R.; Schiller, J. T. Carrageenan is a Potent Inhibitor of Papillomavirus 3360 3292 K. A.; Charman, W. N.; Mayer, A. M. S.; Hamann, M. T. New Infection. PLoS Pathog. 2006, 2, e69. 3361 3293 Manzamine Alkaloids from an Indo-Pacific Sponge. Pharmacokinetics, (325) Hasui, M.; Matsuda, M.; Okutani, K.; Shigeta, S. In Vitro 3362 3294 Oral Availability, and the Significant Activity of Several Manzamines Antiviral Activities of Sulfated Polysaccharides from a Marine Microalga 3363 3295 against HIV-I, AIDS Opportunistic Infections, and Inflammatory (Cochlodinium polykrikoides) against Human Immunodeficiency Virus 3364 3296 Diseases. J. Med. Chem. 2004, 47, 3512−3517. and Other Enveloped Viruses. Int. J. Biol. Macromol. 1995, 17, 293−297. 3365 3297 (307) Peng, J.; Hu, J.-F.; Kazi, A. B.; Li, Z.; Avery, M.; Peraud, O.; Hill, (326) Nakao, Y.; Takada, K.; Matsunaga, S.; Fusetani, N. 3366 3298 R. T.; Franzblau, S. G.; Zhang, F.; Schinazi, R. F.; Wirtz, S. S.; Tharnish, Calyceramides A-C: Neuraminidase Inhibitory Sulfated Ceramides 3367 3299 P.; Kelly, M.; Wahyuono, S.; Hamann, M. T. Manadomanzamines A and from the Marine Sponge Discodermia calyx. Tetrahedron 2001, 57, 3368 3300 B: A Novel Alkaloid Ring System with Potent Activity against 3013−3017. 3369 3301 Mycobacteria and HIV-1. J. Am. Chem. Soc. 2003, 125, 13382−13386. (327) Sun, H. H.; Gross, S. S.; Gunasekera, M.; Koehn, F. E. 3370 3302 (308) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. Weinbersterol Disulfates A and B, Antiviral Steroid Sulfates from the 3371 3303 J.; De Brosse, C.; Mai, S.; Truneh, A.; Carte, B. Novel Alkaloids from the Sponge Petrosia weinbergi. Tetrahedron 1991, 47, 1185−1190. 3372 3304 Sponge Batzella sp.: Inhibitors of HIV gp120-Human CD4 Binding. J. (328) Nakatani, M.; Nakamura, M.; Suzuki, A.; Inoue, M.; Katoh, T. A 3373 3305 Org. Chem. 1995, 60, 1182−1188. New Strategy toward the Total Synthesis of Stachyflin, a Potent Anti- 3374 3306 (309) Hua, H.-M.; Peng, J.; Dunbar, D. C.; Schinazi, R. F.; de Castro Influenza A Virus Agent: Concise Route to the Tetracyclic Core 3375 3307 Andrews, A. G.; Cuevas, C.; Garcia-Fernandez, L. F.; Kelly, M.; Structure. Org. Lett. 2002, 4, 4483−4486. 3376 3308 Hamann, M. T. Batzelladine Alkaloids from the Caribbean Sponge (329) Minagawa, K.; Kouzuki, S.; Yoshimoto, J.; Kawamura, Y.; Tani, 3377 3309 Monanchora unguifera and the Significant Activities against HIV-1 and H.; Iwata, T.; Terui, Y.; Nakai, H.; Yagi, S.; Hattori, N.; et al. Stachyflin 3378 3310 AIDS Opportunistic Infectious Pathogens. Tetrahedron 2007, 63, and Acetylstachyflin, Novel Anti-Influenza A Virus Substances, 3379 3311 11179−11188. Produced by Stachybotrys sp. RF-7260. I. Isolation, Structure Elucidation 3380 3312 (310) Gul, W.; Hammond, N. L.; Yousaf, M.; Bowling, J. J.; Schinazi, R. and Biological Activities. J. Antibiot. 2002, 55, 155−164. 3381 3313 F.; Wirtz, S. S.; de Castro Andrews, G.; Cuevas, C.; Hamann, M. T. (330) Minagawa, K.; Kouzuki, S.; Kamigauchi, T. Stachyflin and 3382 3314 Modification at the C9 Position of the Marine Natural Product Acetylstachyflin, Novel Anti-Influenza A Virus Substances, Produced by 3383 3315 Isoaaptamine and the Impact on HIV-1, Mycobacterial, and Tumor Cell Stachybotrys sp. RF-7260. II. Synthesis and Preliminary Structure- 3384 3316 Activity. Bioorg. Med. Chem. 2006, 14, 8495−8505. Activity Relationships of Stachyflin Derivatives. J. Antibiot. 2002, 55, 3385 3317 (311) Venkateshwar Goud, T.; Srinivasa Reddy, N.; Raghavendra 165−171. 3386 3318 Swamy, N.; Siva Ram, T.; Venkateswarlu, Y. Anti-HIV Active Petrosins (331) Tang, F.; Chen, F.; Li, F. Preparation and Potential In Vivo Anti- 3387 3319 from the Marine Sponge Petrosia similis. Biol. Pharm. Bull. 2003, 26, influenza Virus Activity of Low Molecular-weight κ-carrageenans and 3388 3320 1498−1501. their Derivatives. J. Appl. Polym. Sci. 2013, 127, 2110−2115. 3389 3321 (312) Peng, J.; Walsh, K.; Weedman, V.; Bergthold, J. D.; Lynch, J.; (332) Wang, W.; Zhang, P.; Hao, C.; Zhang, X.-E.; Cui, Z.-Q.; Guan, 3390 3322 Lieu, K. L.; Braude, I. A.; Kelly, M.; Hamann, M. T. The New Bioactive H.-S. In Vitro Inhibitory Effect of Carrageenan Oligosaccharide on 3391 3323 Diterpenes Cyanthiwigins E−AA from the Jamaican Sponge Myrme- Influenza A H1N1 Virus. Antiviral Res. 2011, 92, 237−246. 3392 3324 kioderma styx. Tetrahedron 2002, 58, 7809−7819. (333) Wang, W.; Zhang, P.; Yu, G.-L.; Li, C.-X.; Hao, C.; Qi, X.; Zhang, 3393 3325 (313) Qureshi, A.; Faulkner, D. J. Haplosamates A and B: New L.-J.; Guan, H.-S. Preparation and Anti-Influenza A Virus Activity of κ- 3394 3326 Steroidal Sulfamate Esters from Two Haplosclerid Sponges. Tetrahedron carrageenan Oligosaccharide and its Sulphated Derivatives. Food Chem. 3395 3327 1999, 55, 8323−8330. 2012, 133, 880−888. 3396 3328 (314) Rudi, A.; Yosief, T.; Loya, S.; Hizi, A.; Schleyer, M.; Kashman, Y. (334) Lüscher-Mattli, M.; Glück, R. Dextran Sulfate Inhibits the 3397 3329 Clathsterol, a Novel Anti-HIV-1 RT Sulfated Sterol from the Sponge Fusion of Influenza Virus with Model Membranes, and Suppresses 3398 3330 Clathria Species. J. Nat. Prod. 2001, 64, 1451−1453. Influenza Virus Replication In Vivo. Antiviral Res. 1990, 14,39−50. 3399 3331 (315) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Mode of Inhibition of (335) Ivanova, V.; Rouseva, R.; Kolarova, M.; Serkedjieva, J.; Rachev, 3400 3332 HIV-1 Reverse Transcriptase by Polyacetylenetriol, a Novel Inhibitor of R.; Manolova, N. Isolation of a Polysaccharide with Antiviral Effect from 3401 3333 RNA- and DNA-directed DNA Polymerases. Biochem. J. 2002, 362, Ulva lactuca. Prep. Biochem. 1994, 24,83−97. 3402 3334 685−692. (336) Akamatsu, E.; Shimanaga, M.; Kamei, Y. Isolation of an Anti- 3403 3335 (316) Chill, L.; Rudi, A.; Aknin, M.; Loya, S.; Hizi, A.; Kashman, Y. Influenza Virus Substance, MC26 from a Marine Brown Alga, Sargassum 3404 3336 New Sesterterpenes from Madagascan Lendenfeldia Sponges. Tetrahe- piluliferum and its Antiviral Activity Against Influenza Virus. Coastal 3405 3337 dron 2004, 60, 10619−10626. Bioenvironment 2003, 1,29−34. 3406 3338 (317) Cimino, P.; Bifulco, G.; Casapullo, A.; Bruno, I.; Gomez-Paloma, (337) Haifeng, Z.; Jiangbin, L.; Gan, H. Study on the Inhibition Effects 3407 3339 L.; Riccio, R. Isolation and NMR Characterization of Rosacelose, a of Perna Viridis Polysaccharides on Influenza Virus Reproduction in 3408 3340 Novel Sulfated Polysaccharide from the Sponge Mixylla rosacea. MDCK Cell Cultures. Mod. Med. J. Chin. 2008, 5,4−7. 3409 3341 Carbohydr. Res. 2001, 334,39−47. (338) Wang, W.;Yu, G. L.; Hao, C.; Guan, H. S. Application of 3410 3342 (318) Jiang, B. F.; Xu, X. F.; Li, L.; Yuan, W. Study on “911” Anti-HBV Oligomer Mannuronic Acid in Treating H1N1 of Influenza A Virus. 3411 3343 Effect in HepG2.2.15 Cells Culture. Mod. Prev. Med. 2003, 30, 517−518. CN102488697A, June 13, 2012. 3412

AU DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3413 (339) Guan, H. S. Characteristics and Therapeutic Effects of Propyl (356) Rinehart, K. L.; Kishore, V.; Bible, K. C.; Sakai, R.; Sullins, D. W.; 3480 3414 Mannuronate Sodium Sulfate. CN1088937A, July 6, 1994. Li, K.-M. Didemnins and Tunichlorin: Novel Natural Products from the 3481 3415 (340) Wang, W.; Li, C. X.; Guan, H. S.; Yu, G. L.; Wang, S. X. Marine Tunicate Trididemnum solidum. J. Nat. Prod. 1988, 51,1−21. 3482 3416 Application of Polymannuronic Acid Propyl Ester Sulfate in Preparation (357) Copeland, R.; Balasubramaniam, A.; Tiwari, V.; Zhang, F.; 3483 3417 of Anti-H1N1 Influenza A (H1N1) Virus Medicines. CN102743409A, Bridges, A.; Linhardt, R. J.; Shukla, D.; Liu, J. Using a 3-O-Sulfated 3484 3418 October 24, 2012. Heparin Octasaccharide to Inhibit the Entry of Herpes Simplex Virus 3485 − 3419 (341) Kim, M.; Yim, J. H.; Kim, S.-Y.; Kim, H. S.; Lee, W. G.; Kim, S. J.; Type 1. Biochemistry 2008, 47, 5774 5783. 3486 3420 Kang, P.-S.; Lee, C.-K. In Vitro Inhibition of Influenza A Virus Infection (358) Ramos-Kuri, M.; Barron, R. B. L.; Aguilar-Setien, A. Inhibition of 3487 3421 by Marine Microalga-derived Sulfated Polysaccharide p-KG03. Antiviral Three Alphaherpesviruses (Herpes Simplex 1 and 2 and Pseudorabies 3488 3422 Res. 2012, 93, 253−259. Virus) by Heparin, Heparan and Other Sulfated Polyelectrolytes. Arch. 3489 − 3423 (342) Nagaoka, M.; Shibata, H.; Kimura-Takagi, I.; Hashimoto, S.; Med. Res. 1996, 27,43 48. 3490 3491 3424 Kimura, K.; Makino, T.; Aiyama, R.; Ueyama, S.; Yokokura, T. Structural (359) Neyts, J.; Snoeck, R.; Schols, D.; Balzarini, J.; Esko, J. D.; Van Schepdael, A.; De Clercq, E. Sulfated Polymers Inhibit the Interaction of 3492 3425 Study of Fucoidan from Cladosiphon okamuranus Tokida. Glycoconjugate Human Cytomegalovirus with Cell Surface Heparan Sulfate. Virology 3493 3426 J. 1999, 16,19−26. 1992, 189,48−58. 3494 3427 (343) Hidari, K. I. P. J.; Takahashi, N.; Arihara, M.; Nagaoka, M.; (360) Okazaki, K.; Matsuzaki, T.; Sugahara, Y.; Okada, J.; Hasebe, M.; 3495 3428 Morita, K.; Suzuki, T. Structure and Anti-dengue Virus Activity of Iwamura, Y.; Ohnishi, M.; Kanno, T.; Shimizu, M.; Honda, E.; Kong, Y. 3496 3429 Sulfated Polysaccharide from a Marine Alga. Biochem. Biophys. Res. BHV-1 Adsorption is Mediated by the Interaction of Glycoprotein gIII 3497 3430 Commun. 2008, 376,91−95. with Heparinlike Moiety on the Cell Surface. Virology 1991, 181, 666− 3498 3431 (344) Talarico, L. B.; Damonte, E. B. Interference in Dengue Virus 670. 3499 3432 Adsorption and Uncoating by Carrageenans. Virology 2007, 363, 473− (361) Kari, B.; Gehrz, R. A Human Cytomegalovirus Glycoprotein 3500 3433 485. Complex Designated gC-II is a Major Heparin-Binding Component of 3501 3434 (345) Talarico, L. B.; Pujol, C. A.; Zibetti, R. G. M.; Faria, P. C. S.; the Envelope. J. Virol. 1992, 66, 1761−1764. 3502 3435 Noseda, M. D.; Duarte, M. E. R.; Damonte, E. B. The Antiviral Activity (362) Nan, Y.; Sai, L.; Jian-Jian, H. The Depressive Effect of 3503 3436 of Sulfated Polysaccharides against Dengue Virus is Dependent on Virus Glycosaminoglycan from Scallop on Type-1 Herpes Simplex Virus. 3504 − 3437 Serotype and Host Cell. Antiviral Res. 2005, 66, 103 110. Acta Acad. Med. Qingdao Univ. 2008, 2, 111−114. 3505 3438 (346) Talarico, L. B.; Duarte, M. E. R.; Zibetti, R. G. M.; Noseda, M. (363) Carlucci, M. J.; Scolaro, L. A.; Damonte, E. B. Herpes Simplex 3506 3439 D.; Damonte, E. B. An Algal-Derived DL-Galactan Hybrid is an Efficient Virus Type 1 Variants Arising after Selection with an Antiviral 3507 3440 Preventing Agent for In Vitro Dengue Virus Infection. Planta Med. 2007, Carrageenan: Lack of Correlation Between Drug Susceptibility and 3508 − 3441 73, 1464 1468. Syn Phenotype. J. Med. Virol. 2002, 68,92−98. 3509 3442 (347) Talarico, L. B.; Noseda, M. D.; Ducatti, D. R. B.; Duarte, M. E. (364) Carlucci, M. J.; Ciancia, M.; Matulewicz, M. C.; Cerezo, A. S.; 3510 3443 R.; Damonte, E. B. Differential Inhibition of Dengue Virus Infection in Damonte, E. B. Antiherpetic Activity and Mode of Action of Natural 3511 3444 Mammalian and Mosquito Cells by Iota-Carrageenan. J. Gen. Virol. Carrageenans of Diverse Structural Types. Antiviral Res. 1999, 43,93− 3512 3445 2011, 92, 1332−1342. 102. 3513 3446 (348) Arena, A.; Maugeri, T. L.; Pavone, B.; Iannello, D.; Gugliandolo, (365) Carlucci, M. J.; Pujol, C. A.; Ciancia, M.; Noseda, M. D.; 3514 3447 C.; Bisignano, G. Antiviral and Immunoregulatory Effect of a Novel Matulewicz, M. C.; Damonte, E. B.; Cerezo, A. S. Antiherpetic and 3515 3448 Exopolysaccharide from a Marine Thermotolerant Bacillus licheniformis. Anticoagulant Properties of Carrageenans from the Red Seaweed 3516 3449 Int. Immunopharmacol. 2006, 6,8−13. Gigartina skottsbergii and their Cyclized Derivatives: Correlation 3517 3450 (349) Arena, A.; Gugliandolo, C.; Stassi, G.; Pavone, B.; Iannello, D.; Between Structure and Biological Activity. Int. J. Biol. Macromol. 1997, 3518 3451 Bisignano, G.; Maugeri, T. L. An Exopolysaccharide Produced by 20,97−105. 3519 3452 Geobacillus thermodenitrificans Strain B3-72: Antiviral Activity on (366) Harden, E. A.; Falshaw, R.; Carnachan, S. M.; Kern, E. R.; 3520 3453 Immunocompetent Cells. Immunol. Lett. 2009, 123, 132−137. Prichard, M. N. Virucidal Activity of Polysaccharide Extracts from Four 3521 3454 (350) Baba, M.; Snoeck, R.; Pauwels, R.; De Clercq, E. Sulfated Algal Species against Herpes Simplex Virus. Antiviral Res. 2009, 83, 3522 − 3455 Polysaccharides are Potent and Selective Inhibitors of Various 282 289. 3523 3456 Enveloped Viruses, Including Herpes Simplex Virus, Cytomegalovirus, (367) Damonte, E. B.; Matulewicz, M. C.; Cerezo, A. S. Sulfated 3524 3457 Vesicular Stomatitis Virus, and Human Immunodeficiency Virus. Seaweed Polysaccharides as Antiviral Agents. Curr. Med. Chem. 2004, 3525 − 3526 3458 Antimicrob. Agents Chemother. 1988, 32, 1742−1745. 11, 2399 2419. 3527 3459 (351) Beress,́ A.; Wassermann, O.; Bruhn, T.; Beress,́ L.; Kraiselburd, (368) Kanekiyo, K.; Hayashi, K.; Takenaka, H.; Lee, J.-B.; Hayashi, T. Anti-herpes Simplex Virus Target of an Acidic Polysaccharide, 3528 3460 E. N.; Gonzalez, L. V.; de Motta, G. E.; Chavez, P. I. A New Procedure Nostoflan, from the Edible Blue-Green Alga. Biol. Pharm. Bull. 2007, 3529 3461 for the Isolation of Anti-HIV Compounds (Polysaccharides and 30, 1573−1575. 3530 3462 Polyphenols) from the Marine Alga Fucus vesiculosus. J. Nat. Prod. (369) Canadas’s Source for HIV and Hepatitis C Information 3531 3463 1993, 56, 478−488. [CATIE]. Treatment Update 194. http://www.catie.ca/sites/default/ 3532 3464 (352) Rowley, D. C.; Kelly, S.; Kauffman, C. A.; Jensen, P. R.; Fenical, files/tu194.pdf (accessed April 03, 2013). 3533 3465 W. Halovirs A-E, New Antiviral Agents from a Marine-derived Fungus of (370) Medicines Patent Pool. Patent Status of ARVs. http://www. 3534 3466 the Genus Scytalidium. Bioorg. Med. Chem. 2003, 11, 4263−4274. medicinespatentpool.org/patent-data/patent-status-of-arvs/ (accessed 3535 3467 (353) Kobayashi, J.; Harbour, G. C.; Gilmore, J.; Rinehart, K. L., Jr. April 01, 2013). 3536 3468 Eudistomins A, D, G, H, I, J, M, N, O, P, and Q, Bromo, Hydroxy, ́ β (371) Van Rompay, K. K.; Kearney, B. P.; Sexton, J. J.; Colon, R.; 3537 3469 Pyrrolyl and Iminoazepino -carbolines from the Antiviral Caribbean Lawson, J. R.; Blackwood, E. J.; Lee, W. A.; Bischofberger, N.; Marthas, 3538 − 3470 Tunicate Eudistoma olivaceum. J. Am. Chem. Soc. 1984, 106, 1526 1528. M.L. Evaluation of Oral Tenofovir Disoproxil Fumarate and Topical 3539 3471 (354) Hudson, J. B.; Saboune, H.; Abramowski, Z.; Towers, G. H. N.; Tenofovir GS-7340 to Protect Infant Macaques against Repeated Oral 3540 3472 Rinehart, K. L., Jr. The Photoactive Antimicrobial Properties of Challenges with Virulent Simian Immunodeficiency Virus. JAIDS, J. 3541 3473 Eudistomins from the Caribbean Tunicate Eudistoma olivaceum. Acquired Immune Defic. Syndr. 2006, 43,6−14. 3542 − 3474 Photochem. Photobiol. 1988, 47, 377 381. (372) Eron, J. J., Jr. Antiretroviral Therapy: New Drugs, Formulations, 3543 3475 (355) Sakai, R.; Rinehart, K. L.; Kishore, V.; Kundu, B.; Faircloth, G.; Ideas and Strategies. Top. HIV Med. 2009, 17, 146−150. 3544 3476 Gloer, J. B.; Carney, J. R.; Namikoshi, M.; Sun, F.; Hughes, R. G., Jr.; (373) Gulick, R. M. New Antiretroviral Drugs. Clin. Microbiol. Infect. 3545 3477 Gravalos,́ D. G.; de Quesada, T. G.; Wilson, G. R.; Heid, R. M. Structure- 2003, 9, 186−193. 3546 3478 Activity Relationships of the Didemnins. J. Med. Chem. 1996, 39, 2819− (374) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Jeffrey, S.; Bacheler, L. 3547 3479 2834. T.; Klabe, R. M.; Diamond, S.; Lai, C.-M.; Rabel, S. R.; Saye, J. A.; 3548

AV DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3549 Adams, S. P.; Trainor, G. L.; Anderson, P. S.; Erickson-Viitanen, S. K. Placebo-controlled, Dose-escalation Trial. Lancet 2010, 376, 1467− 3618 3550 Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors 1475. 3619 3551 Inhibit Clinically Relevant Mutant Variants of Human Immunodefi- (389) Cartwright, H. Roche Expands its HCV Pipeline with Anadys 3620 3552 ciency Virus Type 1. Antimicrob. Agents Chemother. 1999, 43, 2893− Pharmaceuticals Acquisition. PharmaDeals Rev 2011, 2011, 109. 3621 3553 2897. (390) Zeuzem, S.; Asselah, T.; Angus, P.; Zarski, J.-P.; Larrey, D.; 3622 3554 (375) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, Müllhaupt, B.; Gane, E.; Schuchmann, M.; Lohse, A.; Pol, S.; 3623 3555 N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. Bronowicki, J.-P.; Roberts, S.; Arasteh, K.; Zoulim, F.; Heim, M.; 3624 3556 C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; Erickson- Stern, J. O.; Kukolj, G.; Nehmiz, G.; Haefner, C.; Boecher, W. O. 3625 3557 Viitanen, S. K. Inhibition of Clinically Relevant Mutant Variants of HIV- Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 3626 3558 1 by Quinazolinone Non-nucleoside Reverse Transcriptase Inhibitors. J. 207127, and Ribavirin in Patients with Chronic HCV Infection. 3627 3559 Med. Chem. 2000, 43, 2019−2030. Gastroenterology 2011, 141, 2047−2055. 3628 3560 (376) Ruiz, N.; Nusrat, R.; Lauenroth-Mai, E.; Berger, D.; Walworth, (391) LaPlante, S. R.; Bös, M.; Brochu, C.; Chabot, C.; Coulombe, R.; 3629 3561 C.; Bacheler, L.; Ploughman, L.; Tsang, P.; Labriola, D.; Echols, R. Study Gillard, J. R.; Jakalian, A.; Poirier, M.; Rancourt, J.; Stammers, T.; 3630 3562 DPC 083-203, a Phase II Comparison of 100 and 200 mg once-daily Thavonekham, B.; Beaulieu, P. L.; Kukolj, G.; Tsantrizos, Y. S. 3631 3563 DPC 083 and 2 NRTIs in Patients Failing a NNRTI-Containing Conformation-Based Restrictions and Scaffold Replacements in the 3632 3564 Regimen. Presented at Program and abstracts of the 9th Conference on Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of 3633 3565 Retroviruses and Opportunistic Infections, Seattle, WA, 2002. Deleobuvir (BI 207127). J. Med. Chem. 2014, 57, 1845−1854. 3634 3566 (377) Allaway, G. P.; Davis-Bruno, K. L.; Beaudry, G. A.; Garcia, E. B.; (392) Boehringer Ingelheim. R&D Pipeline. http://www.boehringer- 3635 3567 Wong, E. L.; Ryder, A. M.; Hasel, K. W.; Gauduin, M.-C.; Koup, R. A.; ingelheim.com/research_development/drug_discovery/pipeline.html 3636 3568 McDougal, J. S.; Maddon, P. J. Expression and Characterization of CD4- (accessed April 05, 2013). 3637 3569 IgG2, a Novel Heterotetramer that Neutralizes Primary HIV Type 1 (393) Summa, V.; Ludmerer, S. W.; McCauley, J. A.; Fandozzi, C.; 3638 3570 Isolates. AIDS Res. Hum. Retroviruses 1995, 11, 533−539. Burlein, C.; Claudio, G.; Coleman, P. J.; DiMuzio, J. M.; Ferrara, M.; Di 3639 3571 (378) Strizki, J. M.; Xu, S.; Wagner, N. E.; Wojcik, L.; Liu, J.; Hou, Y.; Filippo, M.; Gates, A. T.; Graham, D. J.; Harper, S.; Hazuda, D. J.; 3640 3572 Endres, M.; Palani, A.; Shapiro, S.; Clader, J. W.; Greenlee, W. J.; Tagat, McHale, C.; Monteagudo, E.; Pucci, V.; Rowley, M.; Rudd, M. T.; 3641 3573 J. R.; McCombie, S.; Cox, K.; Fawzi, A. B.; Chou, C.-C.; Pugliese-Sivo, Soriano, A.; Stahlhut, M. W.; Vacca, J. P.; Olsen, D. B.; Liverton, N. J.; 3642 3574 C.; Davies, L.; Moreno, M. E.; Ho, D. D.; Trkola, A.; Stoddart, C. A.; Carroll, S. S. MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/ 3643 3575 Moore, J. P.; Reyes, G. R.; Baroudy, B. M. SCH-C (SCH 351125), an 4a Protease with Broad Activity across Genotypes and Resistant 3644 3576 Orally Bioavailable, Small Molecule Antagonist of the Chemokine Variants. Antimicrob. Agents Chemother. 2012, 56, 4161−4167. 3645 3577 Receptor CCR5, is a Potent Inhibitor of HIV-1 Infection In Vitro and In (394) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; 3646 3578 Vivo. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 12718−12723. Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; 3647 3579 (379) Eron, J. J.; Gulick, R. M.; Bartlett, J. A.; Merigan, T.; Arduino, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, 3648 3580 Kilby, J. M.; Yangco, B.; Diers, A.; Drobnes, C.; DeMasi, R.; Greenberg, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: An 3649 3581 M.; Melby, T.; Raskino, C.; Rusnak, P.; Zhang, Y.; Spence, R.; Miralles, HCV NS5A Inhibitor with Broad Genotype Activity. ChemMedChem 3650 3582 G. D. Short-term Safety and Antiretroviral Activity of T-1249, a Second- 2013, 8, 1930−1940. 3651 3583 generation Fusion Inhibitor of HIV. J. Infect. Dis. 2004, 189, 1075−1083. (395) Liverton, N. J.; Carroll, S. S.; DiMuzio, J.; Fandozzi, C.; Graham, 3652 3584 (380) Do Canto, A. M. T. M.; Carvalho, A. J. P.; Ramalho, J. P. P.; D. J.; Hazuda, D.; Holloway, M. K.; Ludmerer, S. W.; McCauley, J. A.; 3653 3585 Loura, L. M. S. T-20 and T-1249 HIV Fusion Inhibitors’ Structure and McIntyre, C. J.; Olsen, D. B.; Rudd, M. T.; Stahlhut, M.; Vacca, J. P. MK- 3654 3586 Conformation in Solution: A Molecular Dynamics Study. J. Pept. Sci. 7009, a Potent and Selective Inhibitor of Hepatitis C Virus NS3/4A 3655 3587 2008, 14, 442−447. Protease. Antimicrob. Agents Chemother. 2010, 54, 305−311. 3656 3588 (381) Rosemond, M. J. C.; St. John-Williams, L.; Yamaguchi, T.; (396) McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.; Nguyen, K. T.; 3657 3589 Fujishita, T.; Walsh, J. S. Enzymology of a Carbonyl Reduction Romano, J. J.; Butcher, J. W.; Gilbert, K. F.; Bush, K. J.; Holloway, M. K.; 3658 3590 Clearance Pathway for the HIV Integrase Inhibitor, S-1360: Role of Swestock, J.; Wan, B.-L.; Carroll, S. S.; DiMuzio, J. M.; Graham, D. J.; 3659 3591 Human Liver Cytosolic Aldo-Keto Reductases. Chem.-Biol. Interact. Ludmerer, S. W.; Mao, S.-S.; Stahlhut, M. W.; Fandozzi, C. M.; Trainor, 3660 3592 2004, 147, 129−139. N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. Discovery of Vaniprevir 3661 3593 (382) Saag, M. S. New and Investigational Antiretroviral Drugs for (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease 3662 3594 HIV Infection: Mechanisms of Action and Early Research Findings. Top. Inhibitor. J. Med. Chem. 2010, 53, 2443−2463. 3663 3595 Antivir. Med. 2012, 20, 162−167. (397) Bechtel, J.; Crosby, R.; Wang, A.; Woldu, E.; Van Horn, S.; 3664 3596 (383) Merck. Merck Pipeline. http://www.merck.com/research/ Horton, J.; Creech, K.; Caballo, L. H.; Voitenleitner, C.; Vamathevan, J.; 3665 3597 pipeline/home.html (accessed April 05, 2013). Duan, M.; Spaltenstein, A.; Kazmierski, W.; Roberts, C.; Hamatake, R. 3666 3598 (384) Garrido, C.; Soriano, V.; de Mendoza, C. New therapeutic In Vitro Profiling of GSK2336805, A Potent and Selective Inhibitor of 3667 3599 strategies for raltegravir. J. Antimicrob. Chemother. 2010, 65, 218−223. HCV NS5A. J. Hepatol. 2011, 54, S307−S308. 3668 3600 (385) GlaxoSmithKline. Our Product Pipeline. http://www.gsk.com/ (398) Merck. Merck Pipeline. http://www.merck.com/research/ 3669 3601 en-gb/research/what-we-are-working-on/product-pipeline/ (accessed pipeline/home.html (accessed August 11, 2014). 3670 3602 April 05, 2013). (399) Margot, N.; Liu, Y.; Babusis, D.; Miller, M. D.; Callebaut, C. 3671 3603 (386) Pockros, P.; Jensen, D.; Tsai, N.; Taylor, R. M.; Ramji, A.; Antiviral Activity of Tenofovir Alafenamide (TAF) against Major NRTI- 3672 3604 Cooper, C.; Dickson, R.; Tice, A.; Stande, S.; Ipe, D.; Thommes, J. A.; resistant Viruses: Improvement over TDF/TFV is Driven by Higher 3673 3605 Vierling, J. M. First SVR Data with the Nucleoside Analogue Polymerase TFV-DP Loading in Target Cells. Presented at the International 3674 3606 Inhibitor Mericitabine (RG7128) Combined with Peginterferon/ Workshop on HIV and Hepatitis Virus Drug Resistance and Curative 3675 3607 ribavirin in Treatment-naive HCV G1/4 Patients: Interim Analysis Strategies, Toronto, Canada, 2013. 3676 3608 from the JUMP-C Trial. J. Hepatol. 2011, 54, S538. (400) Gilead. Pipeline. http://gilead.com/research/pipeline (accessed 3677 3609 (387) Roche Research & Development. Pharma Pipeline. http://www. August 11, 2014). 3678 3610 roche.com/research_and_development/who_we_are_how_we_ (401) Gaggar, A.; Coeshott, C.; Apelian, D.; Rodell, T.; Armstrong, B. 3679 3611 work/pipeline.htm (accessed April 04, 2013). R.; Shen, G.; Subramanian, G. M.; McHutchison, J. G. Safety, 3680 3612 (388) Gane, E. J.; Roberts, S. K.; Stedman, C. A. M.; Angus, P. W.; Tolerability and Immunogenicity of GS-4774, a Hepatitis B Virus- 3681 3613 Ritchie, B.; Elston, R.; Ipe, D.; Morcos, P. N.; Baher, L.; Najera, I.; Chu, specific Therapeutic Vaccine, in Healthy Subjects: A Randomized Study. 3682 3614 T.; Lopatin, U.; Berrey, M. M.; Bradford, W.; Laughlin, M.; Shulman, N. Vaccine 2014, 32, 4925−4931. 3683 3615 S.; Smith, P. F. Oral Combination Therapy with a Nucleoside (402) Lanford, R. E.; Guerra, B.; Chavez, D.; Giavedoni, L.; Hodara, V. 3684 3616 Polymerase Inhibitor (RG7128) and Danoprevir for Chronic Hepatitis L.; Brasky, K. M.; Fosdick, A.; Frey, C. R.; Zheng, J.; Wolfgang, G.; 3685 3617 C Genotype 1 Infection (INFORM-1): A Randomised, Double-blind, Halcomb, R. L.; Tumas, D. B. GS-9620, an Oral Agonist of Toll-like 3686

AW DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3687 Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in (421) Vaidya, A.; Perry, C. M. Simeprevir: First Global Approval. Drugs 3756 3688 Chronically Infected Chimpanzees. Gastroenterology 2013, 144, 1508− 2013, 73, 2093−2106. 3757 3689 1517. (422) Henderson, J. A.; Bilimoria, D.; Bubenik, M.; Cadilhac, C.; 3758 3690 (403) Rossignol, J.-F.; El-Gohary, Y. M. Nitazoxanide in the Treatment Cottrell, K. M.; Denis, F.; Dietrich, E.; Ewing, N.; Falardeau, G.; Giroux, 3759 3691 of Viral Gastroenteritis: A Randomized Double-blind Placebo- S.; L’Heureux, C.; Liu, B.; Mani, N.; Morris, M.; Nicolas, O.; Pereira, O. 3760 3692 controlled Clinical Trial. Aliment. Pharmacol. Ther. 2006, 24, 1423− Z.; Poisson, C.; Reddy, J. T.; Selliah, S.; Shawgo, R. S.; Vaillancourt, L.; 3761 3693 1430. Wang, J.; Xu, J.; Chauret, N.; Berlioz-Seux, F.; Chan, L. C.; Das, S. K.; 3762 3694 (404) Roche. Product Development Portfolio. http://www.roche. Grillot, A.-L.; Bennani, Y. L.; Maxwell, J. P. Synthesis and Evaluation of 3763 3695 com/research_and_development/who_we_are_how_we_work/ NS5A Inhibitors Containing Diverse Heteroaromatic Cores. Bioorg. 3764 3696 pipeline.htm (accessed August 11, 2014). Med. Chem. Lett. 2014, 25, 948−951. 3765 3697 (405) GSK. Our Product Pipeline. http://www.gsk.com/research/ (423) Pilot-Matias, T.; Tripathi, R.; Cohen, D.; Gaultier, I.; Dekhtyar, 3766 3698 what-we-are-working-on/our-product-pipeline.html (accessed August T.; Lu, L.; Reisch, T.; Irvin, M.; Hopkins, T.; Pithawalla, R.; Middleton, 3767 3699 12, 2014). T.; Ng, T.; McDaniel, K.; Or, Y. S.; Menon, R.; Kempf, D.; Molla, A.; 3768 3700 (406) Rossignol, J.-F. Nitazoxanide: A First-in-class Broad-spectrum Collins, C. In Vitro and In Vivo Antiviral Activity and Resistance Profile 3769 3701 Antiviral Agent. Antiviral Res. 2014, 110,94−103. of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450. 3770 3702 (407) Petit, J.; Meurice, N.; Kaiser, C.; Maggiora, G. Softening the Rule Antimicrob. Agents Chemother. 2015, 59, 988. 3771 3703 of Five - Where to Draw the Line? Bioorg. Med. Chem. 2012, 20, 5343− (424) Kati, W.; Koev, G.; Irvin, M.; Beyer, J.; Liu, Y.; Krishnan, P.; 3772 3704 5351. Reisch, T.; Mondal, R.; Wagner, R.; Molla, A.; Maring, C.; Collins, C. In 3773 3705 (408) U.S. Food and Drug Administration. Draft Guidance on Vitro Activity and Resistance Profile of Dasabuvir, a Non-nucleoside 3774 3706 Didanosine. http://www.fda.gov/downloads/Drugs/ HCV Polymerase Inhibitor. Antimicrob. Agents Chemother. 2015, 59, 3775 3707 GuidanceComplianceRegulatoryInformation/Guidances/ucm085597. 1505. 3776 3708 pdf (accessed December 02, 2012). (425) Ghosh, A. K.; Dawson, Z. L.; Mitsuya, H. Darunavir, a 3777 3709 (409) U.S. Food and Drug Administration. Draft Guidance on Conceptually New HIV-1 Protease Inhibitor for the Treatment of Drug- 3778 3710 Zalcitabine. http://www.fda.gov/downloads/Drugs/ resistant HIV. Bioorg. Med. Chem. 2007, 15, 7576−7580. 3779 3711 GuidanceComplianceRegulatoryInformation/Guidances/ucm091313. (426) Black, D. M.; Davis, R.; Doan, B. D.; Lovelace, T. C.; Millar, A.; 3780 3712 pdf (accessed December 01, 2012). Toczko, J. F.; Xie, S. Highly Diastereo- and Enantioselective Catalytic 3781 3713 (410) Bhadury, P.; Mohammad, B. T.; Wright, P. C. The Current Synthesis of the Bis-tetrahydrofuran Alcohol of Brecanavir and 3782 3714 Status of Natural Products from Marine Fungi and their Potential as Darunavir. Tetrahedron: Asymmetry 2008, 19, 2015−2019. 3783 3715 Anti-infective Agents. J. Ind. Microbiol. Biotechnol. 2006, 33, 325−337. (427) Nowicka-Sans, B.; Gong, Y.-F.; McAuliffe, B.; Dicker, I.; Ho, H.- 3784 3716 (411) Yasuhara-Bell, J.; Lu, Y. Marine Compounds and their Antiviral T.; Zhou, N.; Eggers, B.; Lin, P.-F.; Ray, N.; Wind-Rotolo, M.; Zhu, L.; 3785 3717 Activities. Antiviral Res. 2010, 86, 231−240. Majumdar, A.; Stock, D.; Lataillade, M.; Hanna, G. J.; Matiskella, J. D.; 3786 3718 (412) Yin, P. D.; Das, D.; Mitsuya, H. Overcoming HIV Drug Ueda, Y.; Wang, T.; Kadow, J. F.; Meanwell, N. A.; Krystal, M. In Vitro 3787 3719 Resistance through Rational Drug Design Based on Molecular, Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, 3788 3720 Biochemical, and Structural Profiles of HIV Resistance. Cell. Mol. Life the Active Component of the Prodrug BMS-663068. Antimicrob. Agents 3789 3721 Sci. 2006, 63, 1706−1724. Chemother. 2012, 56, 3498−3507. 3790 3722 (413) Greenblatt, D. J. Antiretroviral Boosting by Cobicistat, a (428) Hightower, K. E.; Wang, R.; DeAnda, F.; Johns, B. A.; Weaver, 3791 3723 Structural Analog of Ritonavir. Clin. Pharmacol. Drug Dev. 2014, 3, 335− K.; Shen, Y.; Tomberlin, G. H.; Carter, H. L., III; Broderick, T.; Sigethy, 3792 3724 337. S.; Seki, T.; Kobayashi, M.; Underwood, M. R. Dolutegravir (S/ 3793 3725 (414) Matthews, T.; Salgo, M.; Greenberg, M.; Chung, J.; DeMasi, R.; GSK1349572) Exhibits Significantly Slower Dissociation than Ralte- 3794 3726 Bolognesi, D. Enfuvirtide: The First Therapy to Inhibit the Entry of gravir and Elvitegravir from Wild-Type and Integrase Inhibitor- 3795 3727 HIV-1 into Host CD4 Lymphocytes. Nat. Rev. Drug Discovery 2004, 3, Resistant HIV-1 Integrase-DNA Complexes. Antimicrob. Agents Chemo- 3796 3728 215−225. ther. 2011, 55, 4552−4559. 3797 3729 (415) PDB ID: 1HRH: Davies, J. F., 2nd; Hostomska, Z.; Hostomsky, (429) PDB ID: 3O2D: Freeman, M. M.; Seaman, M. S.; Rits-Volloch, 3798 3730 Z.; Jordan, S. R.; Matthews, D. A. Crystal Structure of the Ribonuclease S.; Hong, X.; Kao, C.-Y.; Ho, D. D.; Chen, B. Crystal Structure of HIV-1 3799 3731 H Domain of HIV-1 Reverse Transcriptase. Science 1991, 252,88−95. Primary Receptor CD4 in Complex with a Potent Antiviral Antibody. 3800 3732 (416) PDB ID: 1EX4: Chen, J. C.-H.; Krucinski, J.; Miercke, L. J. W.; Structure 2010, 18, 1632−1641. 3801 3733 Finer-Moore, J. S.; Tang, A. H.; Leavitt, A. D.; Stroud, R. M. Crystal (430) PDB ID: 4MBS: Tan, Q.; Zhu, Y.; Li, J.; Chen, Z.; Han, G. W.; 3802 3734 Structure of the HIV-1 Integrase Catalytic Core and C-terminal Kufareva, I.; Li, T.; Ma, L.; Fenalti, G.; Li, J.; Zhang, W.; Xie, X.; Yang, 3803 3735 Domains: A Model for Viral DNA Binding. Proc. Natl. Acad. Sci. U. S. A. H.; Jiang, H.; Cherezov, V.; Liu, H.; Stevens, R. C.; Zhao, Q.; Wu, B. 3804 3736 2000, 97, 8233−8238. Structure of the CCR5 Chemokine Receptor-HIV 3805 3737 (417) PDB ID: 2R92: Lehmann, E.; Brueckner, F.; Cramer, P. Maraviroc Complex. Science 2013, 341, 1387−1390. 3806 3738 Molecular Basis of RNA-dependent RNA Polymerase II Activity. Nature (431) PDB ID: 3V6Z: DiMattia, M. A.; Watts, N. R.; Stahl, S. J.; 3807 3739 2007, 450, 445−449. Grimes, J. M.; Steven, A. C.; Stuart, D. I.; Wingfield, P. T. Antigenic 3808 3740 (418) PDB ID: 3HVP: Wlodawer, A.; Miller, M.; Jaskolski, M.; Switching of Hepatitis B Virus by Alternative Dimerization of the Capsid 3809 3741 Sathyanarayana, B. K.; Baldwin, E.; Weber, I. T.; Selk, L. M.; Clawson, Protein. Structure 2013, 21, 133−142. 3810 3742 L.; Schneider, J.; Kent, S. B. Conserved Folding in Retroviral Proteases: (432) PDB ID: 3J2V: Yu, X.; Jin, L.; Jih, J.; Shih, C.; Zhou, Z. H. 3.5Å 3811 3743 Crystal Structure of a Synthetic HIV-1 Protease. Science 1989, 245, 616− cryoEM Structure of Hepatitis B Virus Core Assembled from Full- 3812 3744 621. Length Core Protein. PLoS One 2013, 8, e69729. 3813 3745 (419) National Institute of Allergy and Infectious Diseases. Scanning (433) PDB ID: 2WJ8: Tawar, R.G.; Duquerroy, S.; Vonrhein, C.; 3814 3746 electron micrograph of HIV particles infecting a human T cell. http:// Varela, P. F.; Damier-Piolle, L.; Castagne,́ N.; MacLellan, K.; Bedouelle, 3815 3747 www.nih.gov/science/hiv/full_images/infected1_image.htm (accessed H.; Bricogne, G.; Bhella, D.; Eleoué t,̈ J.-F.; Rey, F. A. Crystal Structure of 3816 3748 November 02, 2014). a Nucleocapsid-like Nucleoprotein-RNA Complex of Respiratory 3817 3749 (420) Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo, H.; Liu, H.; Syncytial Virus. Science 2009, 326, 1279−1283. 3818 3750 Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller, T.; Yang, (434) PDB ID: 2YKD: McPhee, H. K.; Carlisle, J. L.; Beeby, A.; 3819 3751 Z.-Y.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.; Tian, Y.; Money, V. A.; Watson, S. M. D.; Yeo, R. P.; Sanderson, J. M. Influence of 3820 3752 Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. Lipids on the Interfacial Disposition of Respiratory Syncytial Virus 3821 3753 Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Matrix Protein. Langmuir 2011, 27, 304−311. 3822 3754 Inhibitor for the Treatment of Hepatitis C Virus Infection. J. Med. Chem. (435) PDB ID: 4CCF: Peat, T. S. Structure of Respiratory Syncytial 3823 3755 2014, 57, 2033−2046. Virus F Protein Head Domain. DOI: 10.2210/pdb4ccf/pdb. 3824

AX DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX Chemical Reviews Review

3825 (436) PDB ID: 3VTT: Elahi, M.; Islam, M. M.; Noguchi, K.; Yohda, (452) Côte,́ B.; Burch, J. D.; Asante-Appiah, E.; Bayly, C.; Bedard,́ L.; 3893 3826 M.; Kuroda, Y. High Resolution Crystal Structure of Dengue-3 Envelope Blouin, M.; Campeau, L.-C.; Cauchon, E.; Chan, M.; Chefson, A.; 3894 3827 Protein Domain III Suggests Possible Molecular Mechanisms for Coulombe, N.; Cromlish, W.; Debnath, S.; Deschenes,̂ D.; Dupont- 3895 3828 Serospecific Antibody Recognition. Proteins: Struct., Funct., Genet. 2013, Gaudet, K.; Falgueyret, J.-P.; Forget, R.; Gagne,́ S.; Gauvreau, D.; 3896 3829 81, 1090−1095. Girardin, M.; Guiral, S.; Langlois, E.; Li, C. S.; Nguyen, N.; Papp, R.; 3897 3830 (437) PDB ID: 1WYY: Koellhoffer, J. F.; Dai, Z.; Malashkevich, V. N.; Plamondon, S.; Roy, A.; Roy, S.; Seliniotakis, R.; St-Onge, M.; et al. 3898 3831 Stenglein, M. D.; Liu, Y.; Toro, R.; Harrison, J. S.; Chandran, K.; DeRisi, Discovery of MK-1439, an Orally Bioavailable Non-nucleoside Reverse 3899 3832 J. L.; Almo, S. C.; Lai, J. R. Structural Characterization of the Transcriptase Inhibitor Potent against a Wide Range of Resistant 3900 − 3833 Glycoprotein GP2 Core Domain from the CAS Virus, a Novel Mutant HIV Viruses. Bioorg. Med. Chem. Lett. 2014, 24, 917 922. 3901 3834 Arenavirus-like Species. J. Mol. Biol. 2014, 426, 1452−1468. (453) Yoshinaga, T.; Kobayashi, M.; Seki, T.; Miki, S.; Wakasa- 3902 3835 (438) PDB ID: 3I6L: Liu, J.; Wu, P.; Gao, F.; Qi, J.; Kawana- Morimoto, C.; Suyama-Kagitani, A.; Kawauchi-Miki, S.; Taishi, T.; 3903 3836 Tachikawa, A.; Xie, J.; Vavricka, C. J.; Iwamoto, A.; Li, T.; Gao, G. F. Kawasuji, T.; Johns, B. A.; Underwood, M. R.; Garvey, E. P.; Sato, A.; 3904 3837 Novel Immunodominant Peptide Presentation Strategy: A Featured Fujiwara, T. Antiviral Characteristics of GSK1265744, an HIV Integrase 3905 3906 3838 HLA-A*2402-Restricted Cytotoxic T-Lymphocyte Epitope Stabilized Inhibitor Dosed Orally or by Long-acting Injection. Antimicrob. Agents Chemother. 2015, 59, 397. 3907 3839 by Intrachain Hydrogen Bonds from Severe Acute Respiratory (454) Pawlotsky,J.-M.;Najera,I.;Jacobson,I.Resistanceto3908 3840 Syndrome Coronavirus Nucleocapsid Protein. J. Virol. 2010, 84, Mericitabine, a Nucleoside Analogue Inhibitor of HCV RNA-dependent 3909 3841 11849−11857. RNA Polymerase. Antiviral Ther. 2012, 17, 411−423. 3910 3842 (439) PDB ID: 1XJR: Robertson, M. P.; Igel, H.; Baertsch, R.; (455) Jiang, Y.; Andrews, S. W.; Condroski, K. R.; Buckman, B.; 3911 3843 Haussler, D.; Ares, M., Jr.; Scott, W. G. The Structure of a Rigorously Serebryany, V.; Wenglowsky, S.; Kennedy, A. L.; Madduru, M. R.; Wang, 3912 3844 Conserved RNA Element within the SARS Virus Genome. PLoS Biol. B.; Lyon, M.; Doherty, G. A.; Woodard, B. T.; Lemieux, C.; Do, M. G.; 3913 3845 2004, 3, e5. Zhang, H.; Ballard, J.; Vigers, G.; Brandhuber, B. J.; Stengel, P.; Josey, J. 3914 3846 (440) Zhang, X.-N.; Song, Z.-G.; Jiang, T.; Shi, B.-S.; Hu, Y.-W.; Yuan, A.; Beigelman, L.; Blatt, L.; Seiwert, S. D. Discovery of Danoprevir 3915 3847 Z.-H. Rupintrivir is a Promising Candidate for Treating Severe Cases of (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of 3916 3848 Enterovirus-71 Infection. World J. Gastroenterol. 2010, 16, 201−209. Hepatitis C Virus (HCV) NS3/4A Protease. J. Med. Chem. 2014, 57, 3917 3849 (441) Nakajima, M.; DeChavigny, A.; Johnson, C. E.; Hamada, J.; 1753−1769. 3918 3850 Stein, C. A.; Nicolson, G. L. Suramin: A Potent Inhibitor of Melanoma (456) Aghemo, A.; De Francesco, R. New Horizons in Hepatitis C 3919 3851 − Heparanase and Invasion. J. Biol. Chem. 1991, 266, 9661 9666. Antiviral Therapy with Direct-Acting Antivirals. Hepatology 2013, 58, 3920 3852 (442) PDB ID: 3FMG: Aoki, S. T.; Settembre, E. C.; Trask, S. D.; 428−438. 3921 3853 Greenberg, H. B.; Harrison, S. C.; Dormitzer, P. R. Structure of (457) White, P. W.; Llinas-Brunet,̀ M.; Amad, M.; Bethell, R. C.; 3922 3854 Rotavirus Outer-layer Protein VP7 Bound with a Neutralizing Fab. Bolger, G.; Cordingley, M. G.; Duan, J.; Garneau, M.; Lagace,́ L.; 3923 − 3855 Science 2009, 324, 1444 1447. Thibeault, D.; Kukolj, G. Preclinical Characterization of BI 201335, a C- 3924 3856 (443) PDB ID: 2R7R: Lu, X.; McDonald, S. M.; Tortorici, M. A.; Tao, Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A 3925 3857 Y. J.; Vasquez-Del Carpio, R.; Nibert, M. L.; Patton, J. T.; Harrison, S. C. Protease. Antimicrob. Agents Chemother. 2010, 54, 4611−4618. 3926 3858 Mechanism for Coordinated RNA Packaging and Genome Replication (458) Mangion, I. K.; Chen, C.-Y.; Li, H.; Maligres, P.; Chen, Y.; 3927 − 3859 by Rotavirus Polymerase VP1. Structure 2008, 16, 1678 1688. Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; 3928 3860 (444) PDB ID: 1QHD: Mathieu, M.; Petitpas, I.; Navaza, J.; Lepault, J.; Reamer, R. A.; Sherry, B. D.; Zavialov, I. Enantioselective Synthesis of an 3929 3861 Kohli, E.; Pothier, P.; Prasad, B. V. V.; Cohen, J.; Rey, F. A. Atomic HCV NS5a Antagonist. Org. Lett. 2014, 16, 2310−2313. 3930 3862 Structure of the Major Capsid Protein of Rotavirus: Implications for the (459) Kazmierski, W. M.; Maynard, A.; Duan, M.; Baskaran, S.; 3931 3863 Architecture of the Virion. EMBO J. 2001, 20, 1485−1497. Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; 3932 3864 (445) PDB ID: 4IDD: Bornholdt, Z. A.; Noda, T.; Abelson, D. M.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel Spiroketal 3933 3865 Halfmann, P.; Wood, M. R.; Kawaoka, Y.; Saphire, E. O. Structural Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus 3934 3866 Rearrangement of Ebola Virus VP40 Begets Multiple Functions in the Genotype 1b Mutants: From Lead to Clinical Compound. J. Med. Chem. 3935 3867 Virus Life Cycle. Cell 2013, 154, 763−774. 2014, 57, 2058−2073. 3936 3868 (446) PDB ID: 1H2C: Gomis-Rüth, F. X.; Dessen, A.; Timmins, J.; (460) Fosdick, A.; Zheng, J.; Pflanz, S.; Frey, C. R.; Hesselgesser, J.; 3937 3869 Bracher, A.; Kolesnikowa, L.; Becker, S.; Klenk, H.-D.; Weissenhorn, W. Halcomb, R. L.; Wolfgang, G.; Tumas, D. B. Pharmacokinetic and 3938 3870 The Matrix Protein VP40 from Ebola Virus Octamerizes into Pore-like Pharmacodynamic Properties of GS-9620, a Novel Toll-like Receptor 7 3939 3871 Structures with Specific RNA Binding Properties. Structure 2003, 11, Agonist, Demonstrate Interferon-Stimulated Gene Induction without 3940 3872 423−433. Detectable Serum Interferon at Low Oral Doses. J. Pharmacol. Exp. Ther. 3941 − 3873 (447) National Institute of Allergy and Infectious Diseases. Ebola 2014, 348,96 105. 3942 3874 Outbreak Highlights Global Disparities in Healthcare Resources. (461) Fox, L. M.; Saravolatz, L. D. Nitazoxanide: A New Thiazolide 3943 − 3875 http://www.niaid.nih.gov/news/newsreleases/2014/Pages/ Antiparasitic Agent. Clin. Infect. Dis. 2005, 40, 1173 1180. 3944 3876 EbolaDisparities.aspx (accessed November 02, 2014). 3877 (448) PDB ID: 1VCL: Uchida, T.; Yamasaki, T.; Eto, S.; Sugawara, H.; 3878 Kurisu, G.; Nakagawa, A.; Kusunoki, M.; Hatakeyama, T. Crystal 3879 Structure of the Hemolytic Lectin CEL-III Isolated from the Marine 3880 Invertebrate Cucumaria echinata: Implications of Domain Structure for 3881 its Membrane Pore-formation Mechanism. J. Biol. Chem. 2004, 279, 3882 37133−37141. 3883 (449) Delattre, C.; Fenoradosoa, T. A.; Michaud, P. Galactans: An 3884 Overview of their Most Important Sourcing and Applications as Natural 3885 Polysaccharides. Braz. Arch. Biol. Technol. 2011, 54, 1075−1092. 3886 (450) Plaza, A.; Bifulco, G.; Keffer, J. L.; Lloyd, J. R.; Baker, H. L.; 3887 Bewley, C. A. Celebesides A-C and Theopapuamides B-D, Depsipep- 3888 tides from an Indonesian Sponge that Inhibit HIV-1 Entry. J. Org. Chem. 3889 2009, 74, 504−512. 3890 (451) Eisenberg, E. J.; He, G.-X.; Lee, W. A. Metabolism of GS-7340, A 3891 Novel Phenyl Monophosphoramidate Intracellular Prodrug of PMPA, 3892 in Blood. Nucleosides, Nucleotides Nucleic Acids 2001, 20, 1091−1098.

AY DOI: 10.1021/cr4006318 Chem. Rev. XXXX, XXX, XXX−XXX