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ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al., 2018, 2 (2), 73-88

Antiviral and Analogs: A Review

Sawsan Mahmoud1, Sherifa Hasabelnaby1, Sherif F. Hammad1, Tamer M. Sakr2,3*

1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, 11795, Egypt 2Radioactive Isotopes and Generator Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt 3Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), Giza, Egypt

*Corresponding author: Tamer M. Sakr, Radioactive Isotopes and Generator Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt Tel.: +201006884013 E-mail address: [email protected]

Submitted on: 14-06-2017; Revised on: 26-11-2017; Accepted on: 26-11-2017

ABSTRACT are an increasing and probably lasting global risk. Nucleoside and nucleotide analogs represent the largest class of antiviral . Early success in the treatment of human immunodeficiency virus and the recent approval of as phosphoramidate nucleoside prodrug for chronic have provided proof of concept for important this class of compounds as an antiviral agent. This review summarizes the antiviral activity of nucleoside and nucleotide analogs and their recent application.

Keywords: Antiviral; Ebola virus; HCV; Nucleoside; Nucleotide; Zika virus

Nucleoside analogs are the subunits of The modifications in the sugar moiety of deoxyribonucleic acid (DNA) and ribonucleic acid include changes of the sugar substituents, (RNA). They are consisting of a sugar moiety linked to replacement of the oxygen with another atom, addition a purine or pyrimidine base through a β-N-glycosidic of heteroatom in the sugar ring, modifications in ring bond through N9 of the purine and N1 of the pyrimidine size and replacement with acyclic moiety. These heterocyclic base.1 are phosphate ester of alterations may produce remarkable variations in nucleosides, (Figure 1). biological activity and degree of selective toxicity, The purine bases ( and ) and according to their respective chemical and physical the pyrimidine base are common for both RNA properties. Changes of the sugar substituents: and DNA. However, the pyrimidine base uracil is only changes of hydrogen or hydroxyl groups at the 2`-, 3`- found in RNA; whereas , the base-pairing and 4`- positions with other groups have produced equivalent, is found in DNA.1 Invariably, in all compounds with a broad range of biological activity. naturally occurring nucleosides, the configuration at the For example, Zidovudine2 (with azido group at the 3'- anomeric center (C-1`) is β.1 There are two major position) is used for the treatment of HIV. categories: N-nucleosides and C-nucleosides. N- Replacement of the oxygen with another nucleosides are having a bond between the anomeric atom: Replacement of the 4`-ring oxygen with other carbon of the sugar moiety and the nitrogen of the base heteroatoms affect both the conformation and the moiety, whereas C-nucleosides have a bond between biological properties of the nucleoside. Nucleosides the anomeric carbon of the sugar moiety and the carbon whose sugar ring oxygen is replaced by carbon, of the base. The nucleoside analogs can be modified in nitrogen, sulfur, and phosphorus are commonly called their sugar or moieties to develop new drugs carbocyclic nucleosides, azanucleosides, thio- with potent biological activity, (Figure 2). nucleosides, and phosphanucleosides, respectively.

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O Purines Pyrimidines HO P O 5' Base O HO NH O O 4' 1' NH2 O 2 3' 2' Glycosidic bond N N N NH NH NH NH HO OH = ribose H = deoxyribose N N N N NH N O N O N O H H 2 H H H Adenine Guanine Cytosine Uracil Thymine Nucleoside RNA DNA Nucleotide Figure 1. General structure of nucleoside and nucleotide analogs.

Figure 2. General chemical modifications of nucleoside analogs.

Carbocyclic nucleosides, they often display leukemia (Figure 3). Thionucleosides, one of the enhanced biostability because of their stability toward various replacement options for oxygen in the sugar hydrolysis by phosphorylases. This replacement ring of nucleosides is sulfur, which is the most improved enzymatic resistance and reduced toxicity of attractive options. It was hoped that this change in the the carbocyclic nucleosides compared with the size and electronegativity might be tolerated in allowing conventional ones.3 Aristeromycin and Neplanocin A the compounds to retain the activity of their 4`-oxygen are examples of carbocyclic natural products (Figure analogs in addition to be accompanied by decreased 3). Whereas, is an example of FDA approved toxicity and increased metabolic stability as a result of carbocyclic for treatment of HIV as shown in decreased susceptibility to the action of nucleoside Table 1. Azanucleosides, in their original definition, phosphorylases.5 For example, (BVDU) is are nucleoside analogs where the oxygen atom of the known to be a potent and selective inhibitor of herpes furanose ring is replaced by a nitrogen atom. Later on, simplex virus (HSV) type 1 and varicella zoster virus this concept is extended to compounds where the (VZV). However, BVDU is rapidly metabolized to the pyrrolidine core is replaced by piperidine, azetidine or inactive E-5-(2-bromovinyl)uracil and 2-deoxyribose-1- other nitrogen-containing rings, including heterocycles phosphate by pyrimidine nucleoside phosphorylase. In with two heteroatoms, such as , thiazolidinyl contrast, 4`-thio BVDU is resistant to pyrimidine and isoxazolidinyl derivatives. The replacement of the nucleoside phosphorylase and showed a higher heterocyclic core by an acyclic chain containing a chemotherapeutic index than BVDU,6 (Figure 3). nitrogen atom has also been explored, and these Phosphanucleosides, in which the oxygen of the sugar compounds are usually called "acyclic azanucleosides". moiety is replaced by phosphorus atom. Among these Many azanucleosides are potent antiviral, anticancer, analogs, several compounds with anti- activity and agents. For example, forodesine4 is in have recently been discovered.7 advanced clinical trials for the treatment of T-cell http://aprh.journals.ekb.eg/ 74 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al., 2018, 2 (2), 73-88

Figure 3. Examples of therapeutically active nucleoside analogs.

Two heteroatoms in the sugar ring: system. At the beginning of the 90 s, this assumption nucleosides containing sugar moieties with two was reevaluated, and L-nucleoside enantiomers heteroatoms have proven to be quite potent antiviral emerged as a new class of antiviral agents. Although the agents, especially the dioxo- and oxothionucleosides,8 first synthesis of an L- nucleoside was reported in such as (Epivir) which is used for the 1969,14 little attention was paid to L-nucleoside analogs treatment of HIV. Ring size: the isolation of oxetanocin until the discovery of lamivudine in 1995.15 The A,9 a nucleoside which contains an oxetane ring in enantiomers of the natural D-nucleosides, are not place of furanose moiety, from Bacillus megaterium led generally recognized by normal mammalian , to an interest in the synthesis of oxetanocin analogs and but are recognized by virus-encoded or bacterial other nucleosides containing a 4-ring moiety in place of enzymes. This results in minimal toxicity and good the normal furanose sugar (Figure 3).10 Acyclic antiviral/antibacterial activity. Therefore L-nucleoside moiety: the studies had shown that intact sugar was not analogs have recently become of interest in view of necessary to mimic nucleoside binding to the , their potential antiviral activity against HBV12 as leading to the development of acyclic nucleosides. On and . the other hand, they differ from conventional nucleosides in having an acyclic moiety replacing the ▪ Antiviral activity of nucleoside and nucleotide sugar ring. The first acyclic nucleoside to show analogs selective inhibition of HSV replication was acyclovir, a Recently, we are facing an outburst of new and -based nucleoside whose clinical emerging viral diseases, as new strains of hepatitis and effectiveness as an antiviral agent has stimulated a large herpes , West-Nile virus, Zika virus, and some interest in acyclic nucleosides.11 exotic viruses that have the potential for a The modifications in the base moiety of outbreak. Nucleoside analogs have been the drugs of nucleoside analogs have resulted in a variety of choice in the treatment of several diseases caused by therapeutic applications. There are different strategies virus (HSV), human in the modification of the nucleobase such as (HCMV), varicella zoster virus (VZV), human halogenation like 2`-3`-dideoxy-5-fluoro-3`-thiacytidine immunodeficiency virus type 1 (HIV-1) and human (Emtricitabine),12 or as purine modification like 1,2,4- (HBV) and C (HCV) virus16. Currently, triazole-3-carboxamide analogue (),13 which is there are over twenty FDA approved nucleoside and used to stop viral RNA synthesis (Table 1). nucleotide analogs that are used as antiviral agents for L-nucleosides, for a long time, it was assumed several infections such as different types of viral that nucleoside analogs have been only D-configuration hepatitis, human immunodeficiency virus infection and and could exhibit biological activity owing to the acquired immune deficiency syndrome (HIV/AIDS) believed stereospecificity of enzymes in the living and herpes virus infections,16 (Table 1). http://aprh.journals.ekb.eg/ 75 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al., 2018, 2 (2), 73-88

Table 1. FDA approved nucleos(t)ide analogs as antiviral drugs

Structure Compound Virus Company

Idoxuridine, IDU, Herplex HSV, VZV GSK, 80s, no FDA label

Edoxudine, EDU, Aedurid HSV Upjohn, 1969

Trifluridine, TFT, Viroptic HSV King Pharmaceutical 1980

Parkedale pharmaceuticals, , Ara-A, Vira-A HSV, VZV no FDA label

Berlin Chemie, 80s, no FDA Brivudine, BVDU, Helpin HSV, VZV label

HSV, VZV Acyclovir, ACV, GSK, 1982

Ganciclovir, GCV, Cytovene CMV Hoffmann-La Roche, 1989

Valaciclovir, VACV, V altrex HSV, VZV, CMV GSK, 1996

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Gilead Sciences and Pfizer, , CDV, Vistide CMV in AIDS 1996

Valganciclovir, VGCV, CMV Hoffmann-La Roche, 2001 Valcyte

Penciclovir, PCV, Denavir HSV Novartis, 2002

Famciclovir, FCV, Famvir HSV Novartis, 2007

Zidovudine, AZT, Retrovir HIV GSK, 1987

Didanosine, ddI, Videx HIV BMS, 1991

Zalcitabine, ddC, Hivid HIV Hoffmann-La Roche, 1992

Stavudine, d4T, Zerit HIV BMS, 1994

Abacavir, ABV, Ziagen HIV GSK, 1998

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Lamivudine, 3TC, Epivir HIV then HBV GSK, 1995

Emtricitabine, FTC, Emtriva HIV, then HBV , 2003

Tenofovir disoproxil fumarate, HIV, then HBV Gilead Sciences, 2008 TDF, Viread

Tenofovir alafenamide HIV, HBV Gilead Sciences, 2015 fumarate, TAF, vemlidy

Adefovir dipivoxil, ADV, HBV Gilead Sciences, 2003 Hepsera

Entecavir, ETV, Baraclude HBV MS, 2004

Telbivudine, LdT, Tyzeka HBV Novartis, 2006

HCV, , First developed by ICN , Ribavirin, RBV, Virazole Pharmaceuticals, 1980, no hemorrhagic FDA label viruses, RSV

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Sofosbuvir, Sovaldi HCV Gilead Sciences, 2013

The era of started with leads to the production of a monophosphate metabolite. (IDU). In 1959, it was synthesized by A second phosphorylation step is then performed by Prusoff as a potential anticancer drug.17 Furthermore, it nucleoside monophosphate kinase, and the third was shown in 1961 to possess activity against HSV by phosphorylation step is performed by nucleoside Herrmann.18 IDU is still used in the topical treatment of diphosphate kinase. Triphosphorylated nucleosides are herpetic eye infections. After that, a variety of the active forms of these drugs and they act as inhibitors biologically interesting and promising nucleosides have for intracellular essential enzymes, such as viral been discovered, some of them are being used clinically polymerases or act as a substrate for the viral enzyme or are undergoing preclinical or clinical development. and incorporated into newly synthesized nucleic acid by The 2`-deoxynucleosides as Idoxuridne (IDU),18 competition with their normal counterparts. The (TFT),19 (EDU),20 Vidarabine incorporation of nucleoside or nucleotide analogs into and Brivudine21 (BVDU) have been used for the DNA or RNA may induce either the termination of treatment of herpes viruses as DNA polymerase chain elongation or the accumulation of mutations in inhibitors. Acyclic nucleosides as Acyclovir (ACV), the viral progeny.16 (GCV), (VACV), Cidofovir In addition to participation in RNA (CDV), (VGCV), (PCV) as the substrates, nucleoside 5`- and (FCV) have been used for the triphosphates (NTPs) are involved in many biological treatment of herpes viruses (Table 1).22 regulations and pathways. To transcribe and The 2`,3`-dideoxynucleosides (ddNs) have investigate the biological systems, many native and proved to be the most effective therapeutic agents modified NTPs are synthesized either chemically or against HIV because the absence of 3`-hydroxyl group enzymatically. Since the first chemical synthesis of can be lead to the termination of DNA sequence such as NTPs was accomplished six decades ago,29 a large (AZT), (ddI), number of chemical strategies have been developed to (ddC), Stazudine (d4T)23 and Abacavir24 (ABV). L- effectively synthesize nucleoside triphosphates in the nucleosides as Lamivudine (3TC) and Emtricitabine past decades. Because of the drawbacks of enzymatic (FTC) and acyclic nucleoside prodrugs as Tenofovir synthesis, such as the substrate specificity, yield and disoproxil fumarate (TDF), cost, chemical synthesis is still a better choice for (TAF)25 have been used for the treatment of HIV and preparing a large quantity of nucleoside triphosphates, HBV as inhibitors. especially those with modifications.30 In spite of many dipivoxil (ADV), (ETV) and Telbivudine synthetic strategies developed including one-pot (LdT)26 have been approved for treatment of HBV as synthesis such as Yoshikawa protocol,31-33 Ludwig and reverse transcriptase inhibitors. Ribavirin13 (RBV) was Eckstein protocol34,35 and Borch protocol, 36 a approved for medical use in 1986 and used to treat convenient synthesis of the 5`-triphosphates directly hepatitis C and viral hemorrhagic fever. Currently, from unprotected nucleosides with high regioselectivity Sofosbuvir (SOF) 27 has been approved for the treatment still remains a challenge. 30 of HCV as non-structural 5B (NS5B) polymerase inhibitor. Nucleoside monophosphate prodrugs These nucleoside analogs depend on cellular Mechanism of action of nucleoside analogs kinases to undergo addition of phosphate groups to Therapeutic nucleoside and nucleotide analogs form the corresponding active have the same metabolic pathways as endogenous to express their therapeutic effects.37 However, nucleosides and nucleotides (Figure 4). Nucleoside and nucleoside triphosphates cannot be considered as a nucleotide analogs enter cells through specific viable drugs as they usually have poor chemical nucleoside transporters.28 Inside the cell, the nucleoside stability with a high polarity that prevent them from analog undergoes an initial rate-limiting transporting across cell membranes. During the phosphorylation step by a nucleoside kinase, which nucleoside analog phosphate activation process, the first

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Figure 4. Mechanism of action of nucleoside analogs16.

Figure 5. General strategy for nucleoside prodrug16.

O O O O P O Nu O P C Nu O O P Nu O O n m O Phosphate Alkoxyalkyl

O ROOC O O N P Nu ROOC ROOC H N P O Nu N P C Nu NH H H O O COOR Phosphoramidate Phosphonamidate Phosphordiamidate or Phosphondiamidate

Figure 6. Functional group names of P (V) moieties.

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Figure 7. Phosphoramidate prodrugs in clinical trials or FDA approved.

Figure 8. of phosphoramidate prodrugs.

Scheme 1. Mechanism of synthesis of phosphoramidates nucleosides. http://aprh.journals.ekb.eg/ 81 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al., 2018, 2 (2), 73-88

Scheme 2. Synthesis of phosphorylating reagents.

Figure 9. Examples of nucleos(t)ide HCV NS5B polymerase inhibitors.

phosphorylation has been identified as the rate-limiting "ProTides", contain a phosphorus atom linked to an step, which led medicinal chemists to prepare stable amino acid alkyl ester and an aryloxy group. In the protected monophosphate nucleosides able of delivering early 1990s by McGuigan38 and co-workers, this nucleoside monophosphates intracellularly. These prodrug approach was development as a result of nucleoside monophosphate prodrugs are designed to several years of SAR studies during which several types pass the biological barriers and reach the targeted cells of masked phosphate moieties were evaluated as or tissues. Once inside the cell, the protecting groups bis(alkyloxy) and haloalkyloxyphosphates, are then degraded enzymatically and/or chemically, bis(aryloxyphosphate), cyclic and noncyclic releasing the nucleoside analog in the monophosphate alkyloxyphosphoramidates. form, which can efficiently express its therapeutical Phosphoramidate prodrugs approach has the potency by intracellular conversion to the ability to increase the activity of nucleosides, and also corresponding nucleoside triphosphate (Figure 5). they are relatively easy to prepare. After the approval of Several strategies allowing intracellular sofosbuvir, the development of several delivery of nucleotide analogs were developed over the phosphoramidate prodrugs has now advanced to clinical past 20 years based on the design of many different trials for HCV treatment as (INX-08189 and PSI- types of nucleoside monophosphate prodrugs including: 353661), HIV treatment (as ) and cancer (as nucleoside phosphates and , thymectacin) as shown in Figure 7. phosphoramidate and phosphonamidate, alkoxy alkyl The metabolism of these phosphoramidate monoester and phosphorodiamidates and prodrugs,37 leading to the intracellular delivery of active phosphonodiamidates (Figure 6).37 Currently, nucleoside monophosphates, has been studied in detail phosphoramidate prodrugs are the most important over the years. After crossing the cell membrane, the approach after the FDA approval of Sofosbuvir. monophosphate deprotection is initiated by an esterase

or cathepsin A producing carboxylate I. The Phosphoramidate Prodrugs intermediate I is exposed to spontaneous intramolecular Aryloxyphosphoramidate prodrugs, also called cyclized to form a five-member ring II, followed by http://aprh.journals.ekb.eg/ 82 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al., 2018, 2 (2), 73-88 releasing a molecule of phenol. Cyclic intermediate II endogenous nucleotide substrate.42 Therefore, undergoes chemical opening in the presence of water Sofosbuvir and related 2`-C-methylated derivatives leading to phosphoramidate diester III. Finally, with a hydroxyl group or fluorine atom at the 2`- cleavage of intermediate III by intracellular position act as potent chain terminators, such as PSI- phosphoramidase frees the nucleoside monophosphate. 6130,43-51 Mercitabine,52-61 IDX18462,68, Then, consecutively phosphorylated to diphosphate and ,69-72 R-1479 and its prodrug Balapiravir to active triphosphate metabolite by kinase enzyme, R-162673-79 as shown in Figure 9. (Figure 8). General mechanism of synthesis of Nucleosides against Ebola phosphoramidate nucleoside prodrugs has been reported The imino-C-nucleoside BCX4430 is used as a by coupling of nucleosides with phosphorochloridate by potential therapeutic for the treatment of Ebola virus either activation of the imidazolium intermediate with infections, it showed a promising result in vitro studies NMI (N-methyl imidazole) 39 or by 5′- deprotonation of and it is in phase 1 trial. It is designed by Biocrst the nucleoside with t-BuMgCl 40 and subsequent Pharma. The BXC 4430’s mechanism of action is that it substitution with the chlorophosphoramidate (Scheme is taken up by viral RNA polymers and halts the RNA 1). replication. In vitro studies it showed promising results Over the past twenty years, substitutions of the against Ebola Virus.80-82 phosphorochloridate reagents have been explored by modifying: 1. The nature of the aryloxy portion (substituted phenols or naphthols). 2. The amino acid. (commonly L-alanine) 3. The amino acid ester. (i-propyl ester or ethyl ester) Phosphorochloridate is the term used to refer to the phosphorylating reagents used for the coupling with the nucleosides. According to the procedure of Nucleosides against dengue and zika Curly et al.,41 these were obtained from the low A lot of nucleoside analogs have been tested temperature (-78 oC) coupling of aminoacid ester against , but it was found that the hydrochloride salts with phenyl dichlorophosophate in inhibitory effects of valganciclovir and the presence of TEA in anhydrous DCM (Scheme 2). against dengue suggest that they may be explored Phosphorochloridates are generally obtained as a 1:1 further as antiviral agents aganist dengue infection and mixture of R and S diastereoisomers. From all of the p p lead in the development of new analogs in targeting natural amino acids, L-alanine is commonly used, dengue infections.83 It was reported that 2`-C- whereas the nature of the aryl group and carboxyl ester methylated nucleosides exerted activity against ZIKV portion is dependent on the nucleoside and/or its under in vitro conditions. These compounds provide a application. basis for structure-based optimization and rational design of effective prodrugs, which will be further ▪ Recent FDA approved and clinical trials antiviral tested in rodent models for therapy of ZIKV infection.84 nucleoside and nucleotide analogs Nucleos(t)ides against HCV Conflict of Interest 27 Sofosbuvir has highly potent clinical anti-HCV The authors declare that they don’t have any activity across all genotypes. Sofosbuvir is a conflict of interest. phosphoramidate prodrug that initially yields a monophosphate metabolite following intracellular REFERENCES hydrolysis, which is further converted to its diphosphate then to its active triphosphate form that binds to the 1. Nelson, D.; Cox, M. Lehninger Principles of active site of NS5B. Sofosbuvir contains the 2ʹ-fluoro- Biochemistry 4th Edn.; Worth, New York, USA, C-methyl sugar moiety; is currently the only one 2005, pp 273-305. received FDA approval in December 2013 as nucleotide 2. 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