Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 Timeline of some major epidemics/pandemics in human history Quick facts: • From wikipedia: • An epidemic is the rapid spread of a disease to a large number of ~ 400 BC Plague of Athens (Greece, possibly typhus) people in a given population within a short period of time. 165-180 Antonine Plague (Roman Empire, possibly smallpox) • A pandemic is a serious epidemic that has spread over a large region and/or affects a substantial number of people. 250-266 Plague of Cyprian (Europe, possibly smallpox) • The most fatal pandemic in human history was the Black Death, which resulted in an estimated 75-200 million deaths (1/3 of European population) 541-542 Plague of Justinian (Europe, plague) • Major diseases that were responsible for outbreaks: • Medication available: plague, tuberculosis, influenza, malaria, cholera, 735-737 Japanese smallpox epidemic (Japan, smallpox) leprosy, AIDS/HIV • Only vaccines: measles, smallpox, typhus, yellow fever, Ebola 1300s Black Death (Europe, plague) • No treatments available: coronavirus (SARS, MERS, COVID-19) 1600s Italian plague (Italy, plague) Compartment model in epidemiology: • The simplest model for a disease outbreak is the SIR model, where: Great plague of London (England, plague) • S = number of Susceptibles • I = number of Infected Great plague of Vienna (Austria, plague) • R = number of Recovered (or deceased) S, I and R are all functions with respect to time t susceptible Great plague of Marseille (France, plague) recovered 1700s • Rates of change for S, I, and R: Persian plague (Persia, plague) (β = avg. number of social encounters, I/N = avg. prob. of encoutering a patient) 1800s Ottoman plague epidemic (Ottoman empire, plague) infected (γ = the rate at which patients recover/die) 1st, 2nd and 3rd cholera pandemic (worldwide, cholera) http://jsxgraph.uni-bayreuth.de/wiki/ 1889-1890 flu pandemic (worldwide, influenza) index.php/Epidemiology:_The_SIR_model 1900s Manchurian plague (China, Pneumonic plague) • Controlling the infected curve is crucial to pandemic management https://en.wikipedia.org/ Spanish flu (worldwide, influenza) wiki/Pandemic Asian flu (worldwide, influenza) • Containment • Mitigation Hong Kong flu (worldwide, influenza) • Suppression HIV/AIDS pandemic (worldwide, HIV/AIDS) 2000s 2004-04 SARS outbreak (worldwide, SARS) • The basic reproduction number (R0): the expected number of cases generated by one case in a population where all individuals are still susceptible. 2009 flu pandemic (worldwide, influenza) • Not to be confused with the effective reproduction number (R) Measles 12-18 • When R > 1, the disease spreads 2012 MERS outbreak (worldwide, MERS) Chickenpox 10-12 • When R < 1, the outbreak is under controll and will die out Rubella 5-7 • Importance of vaccination: decrease R (herd immunity) Ebola virus epidemic (west Africa, Ebola) Smallpox 3.5-6 This GM covers: Zika virus epidemic (worldwide, Zika virus) COVID-19 1.4-5.7 • Basic information of epidemics/pandemics HIV/AIDS 2-5 • Several viral epidemics (influenza, HIV, coronavirus) present 2019-20 coronavirus pandemic (worldwide, COVID-19) Common cold 2-3 • Associated antiviral drugs and their synthesis Influenza (1918) 1.4-2.8 = over 100,000 deaths Not covered: Seasonal flu 0.9-2.1 • Bacterial or parasitic diseases = over 1 million deaths • Antibiotics Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 https://www.cdc.gov/flu/about/index.html Influenza Virus: https://micro.magnet.fsu.edu/cells/ Influenza viruses/influenzavirus.html • An infectious respiratory disease caused by the influenza virus • Belongs to orthomyxoviridae, a family • Common symptoms include high fever, runny nose, sore throat, muscle and joint pain, of RNA viruses • Four distinct genera: A, B, C, and D headache, coughing, and fatigue • Some structural charateristrics: • Shares many symptoms with common cold. However, common cold is mostly caused • Lipid envelop by human rhinovirus and its symptoms are usually milder. (why rubbing alcohol disinfects) • A yearly outbreak pattern: October to May considered flu season in the US • Nucleoprotein: 8 pieces of single- • 300k - 650k deaths annually; over 3 million cases of severe illness stranded RNA packed with proteins • On average, about 8% of the U.S. population gets flu every season • Hemagglutinin (HA) and neuraminidase • Pandemic severity index (PSI): a level 1 to 5 scale for severity of influenza pandemics (NA): important surface glycoproteins for based on the case fatality rate. Level 5 has the highest case fatality rate of >2.0%. host cell recognition and viral replication. Also the major antigens to trigger immune responses. Pandemic History: J. Appl. Microbiol. 2001, 91, 572–579 Serotypes: • First confirmed record of an influenza epidemic dates back to 1500s • Antigenic shift: mutations and reassortments of viral strains can lead to structural • Responsible for several major outbreaks since the 20th century changes in HA and NA, resulting in different antigenic properties. Case Pandemic • Only observed in influenza A viruses Name Date Deaths fatality rate severity index • Influenza A serotypes are denoted as HxNy • x and y are arbitrary numbers denoting the types of HA and NA 1918 flu pandemic • A total of 18 different types of HA and 11 different types of NA were identified (Spanish flu) 1918-1919 17-50 million 2-3% 5 • Out of the 198 possible permutations, 131 serotypes were found in nature Asian Flu 1957-1958 1-1.5 million 0.13% 2 • Trivia: match the influenza serotype with the corresponding epidemics/pandemics Hong Kong Flu 1968-1969 0.75-1 million <0.1% 2 2009 swine flu H1N1 2009 flu pandemic 2004 avian flu/bird flu (swine flu) 2009-2010 100k - 400k 0.03% N/A H2N2 1968 Hong Kong flu H3N2 The 1918 Flu Pandemic: Emerg Infect Dis. 2006, 12, 15–22. • Origin was disputed; hypotheses include Kansas or European troops in WWI 1957 Asian flu H5N1 • Around 500 million people were infected globally, around 1/3 of the world’s population 1918 Spanish Flu H7N9 • A unique (and not explained) feature is the high mortality rate among young adults • Public places were closed and quarantines were enforced; “social distancing” Mechanism of Action: Front. Immunol. 2018, 9, 1581 • Mutation of the virus was observed between the “waves” • Transmission usually occurs through aerosols (coughs, sneezes, etc.), less commonly of outbreaks through saliva, bodily fluids and feces. • Massive troop movements during WWI likely accelerated • Step 1: Viral HA binds to the epithelial cell, causing the the pandemic and selected for more virulent strains. virus being imported by endocytosis • Died out quickly in early 1919 • Step 2: Viral RNA and RNA polymerases are • Genetic mapping of the virus made possible after Johan released into the cytoplasm and relocate Hultin’s discovery of body samples stored in the permafrost to the nucleus. near Brevig Mission, a remote Alaskan village • Step 3: RNA replication in the nucleus (https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virus.html) • Step 4: Viral mRNA re-enters the cyto- plasm and is translated by ribosomes • Step 5: Viral proteins are transported to the cell membrane (HA and NA) or stay the cytoplasm for inhibition of normal cell activity • Step 6: Viral RNA and proteins aggregates near the cell membrane and forms a protusion • Step 7: The new virus detaches (facilitated by NA) by exocytosis, usually followed by death of host cell (https://en.wikipedia.org/ wiki/Orthomyxoviridae) Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 OH O O Clin. Microbiol Rev. 2016, 29, 695–747 All Approved Antiviral Drugs for Influenza: For a useful review of viral NA inhibitors, see: O O Molecules 2016, 21, 1513 HO OH Me OEt NH2 OH HN Me HN F HN NH2 NH2 Me O Me O S F NH Oseltamivir (Tamiflu®) ® O ® Amantadine (Symmetrel ) Zanamivir (Relenza ) Gilead, FDA Approv. 1999 FDA Approv. 1968 F N GSK, FDA Approv. 1999 O H NH2 N N O OMe O NH OH N OH Me NH O N 2 ® HO OH H N O Favipiravir (Avigan ) 2 N OH Toyama Chemical OH H MeO O O O Approv. 2014 (Japan) HN Me NH HN NH2 O Me O Baloxavir marboxil (Xofluza®) ® Me O Me Rimantadine (Flumadine ) NH Shionogi & Roche, FDA Approv. 2018 FDA Approv. 1994 Laninamivir (Inavir®) Peramivir (Rapivab®) Daiichi Sankyo, Approv. 2010 (Japan) BioCryst, FDA Approv. 2014 M.2 protein inhibitors RNA polymerase inhibitor Neuroaminidase (NA) inhibitors Cap-dependent endonuclease inhibitor Selected Syntheses: First Synthesis by von Itzstein: OAc OH OH + O CO2Et OH O OH EtOH, H OH Ac O, AcOH AcO TMSN3, tBuOH O 80°C O 2 HO HO 80 °C O CO2H CO2Et OAc HO OH OH 93% OH 72% N 85% AcHN AcHN OH O HN OH OH OAc Me N-acetylneuraminic acid ($47/g) HN NH2 Me O O CO2Et 1) KOH OAc 1) H2, Lindlar cat. AcO NH O CO Et 2) TFA Zanamivir 2 NBoc OAc Zanamivir AcO 2) AcHN Shibasaki’s Synthesis: OAc (6 steps, 30%-50% overall) AcHN MeS NHBoc HN NBoc NO HgCl2, Et3N 2 N3 NHBoc + 85% over 2 steps Carbohydr. Res. 1994, 259, 301–305. PMBO CHO Nd5O(OiPr)13 NaHMDS OBn OTBS 1) OsO OBn OTBS CO2Me -60 °C, 71% OH 10 steps 4 2) NaIO (next page) 3% of: iPr BnO 4 BnO O H OH PMBO OTBS HO N 3) Wittig N NO 22% overall OBn NHAc OBn NHAc H O 2 F F Angew. Chem. Int. Ed. 2012, 51, 1644–1647 Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 O OAc 1) H , Pd/C OBn 2 1) Bu NF, AcOH 2) Ac O OAc Ph O CO2Et 4 2 O AcO 2) BF •OEt O CO2Me 79% over 4 steps Ac2O, AcOH 3 2 O CO2Me OAc BnO AcO Zanamivir OBn 3) PhCO2tBu N same steps as CuBr, reflux OAc AcHN AcHN O von Itzstein et al Me Me Ma’s synthesis: Me 20 mol% cat.