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Symmetrel (Amantadine)

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Symmetrel (Amantadine) An#virals Lecture 20 Biology W3310/4310 Virology Spring 2015 You can’t go back and you can’t stand s0ll. If the thunder don’t get you, then the lightning will. JERRY GARCIA The Wheel (lyrics by Robert Hunter) Vaccines can prevent viral disease • But they Have modest or no therapeuMc effect if an individual is already infected (excepMon?) • Our second arm of anMviral defense is anMvirals • Can stop infecMon once it Has started Despite 50 years of research, our arsenal of an#viral drugs remains dangerously small Only about 100 an0viral drugs are available on the US market Most against HIV, HCV, herpesviruses - Persistent infecons Example of approved Target Virus compound Attachment HIV Maraviroc Uncoating Influenza A Amantadine, rimantadine Acyclovir, valacyclovir, DNA polymerase Herpesviruses cidofovir Reverse transcriptase HIV Zidovudine, nevirapine HIV Saquinavir, ritonavir Viral protease HCV Telaprevir, boceprevir Neuraminidase Influenza A and B Zanamavir, oseltamivir Why are there so few anviral drugs? • Compounds interfering with virus growth can adversely affect the Host cell - Side effects are common (unacceptable) - Every step in viral life cycle engages host funcons • Some medically important viruses can’t be propagated, Have no animal model, or are dangerous - HBV, HPV, norovirus - Smallpox - Ebola, Lassa An unappreciated third reason may be the most important • A compound must block virus replicaMon completely! It must be potent • Many standard pHarmaceuMcals can be effecMve if enZyme acMvity is parMally blocked • ParMal inHibiMon is not acceptable for an anMviral drug - resistant mutants will arise • Makes drug discovery expensive Principles of Virology, ASM Press Another serious problem for an#viral discovery: Many acute infecons are of short dura0on • By the Mme the paMent feels ill, it is too late to impact clinical disease • AnMviral drugs for these viruses must be given early in infecMon or propHylacMcally to populaMons at risk - Safety issues; giving drugs to healthy people not wise • No broad-spectrum anMviral agents are currently available • Lack of rapid diagnosMc reagents Has Hampered development of anMviral drugs LJ1001, a broad spectrum an#viral hp://www.ncbi.nlm.niH.gov/pubmed/20133606 LJ1001, a broad spectrum an#viral An#viral history • THe first modest searcH for anMviral drugs occurred in the early 1950s - Chemists looked at deriva0ves of the sulfonamide an0bio0cs - Synthesis of thiosemicarbazones acve against poxviruses - Smallpox was s0ll a major threat aUer WWII • 1960s and 1970s: “blind screening” programs to find cHemicals with anMviral acMvity - Spurred on by successes in the treatment of bacterial infecons with an0bio0cs Blind screening • No a]empt to focus discovery on a virus or a virus-specific mecHanism • Random cHemicals and natural product mixtures tested for ability to block replicaMon of a variety of viruses in cell culture systems • Hits, compounds or mixtures that block in vitro viral replicaMon; purified and fracMons tested in various cell culture and animal models for safety and efficacy • Promising molecules called leads were modified systemaMcally by medicinal cHemists - To reduce toxicity, increase solubility and bioavailability - To improve other pharmacokine0c proper0es Thousands of molecules were made and screened before a specific an#viral was even tested in humans • Considerable effort, very li]le success • One excepMon: Symmetrel (amantadine) - Approved late 1960s for treatment of influenza A virus infecons - One of three drugs now available for influenza • MecHanism of acMon was oien unknown or speculaMve - Mechanism of acon of Symmetrel deduced early 1990s An#viral discovery today • Recombinant DNA tecHnology & sopHisMcated cHemistry make targeted discovery possible • EssenMal viral genes cloned, expressed in geneMcally tractable organisms, purified, analyZed in atomic detail • Life cycles of most viruses known, targets for intervenMon can be generaliZed • Modern tecHnology allows inHibitors to be found even for viruses that cannot be propagated in cell culture • Blind screening procedures are dead Some targets for an#viral drug discovery Fusion inHibitors (HIV) Entry inHibitor (influenZa) Interferon (HepaMMs C) Nucleoside, non- nucleoside analogs (HIV, HCV, herpesvirus) Protease inHibitors (HIV, HCV) NA inHibitors (influenZa) Principles of Virology, ASM Press The path of drug discovery •Will the compound get to the rigHt place in the body at the rigHt concentraMon? (bioavailability) Will the compound persist in the proof of principle • body long enough to be effecve? (pHarmacokineMcs) •Will the compound be safe? (toxicity and specificity) Principles of Virology, ASM Press Significant hurdles stand in the way of finding effec#ve an#viral drugs It is not unusual for the cost to bring an anMviral drug to market to exceed $100-200 million dollars! Principles of Virology, ASM Press Mechanism-based screens Principles of Virology, ASM Press Cell-based screen Principles of Virology, ASM Press An#viral screening • HigH-througHput: 10,000 compounds/day • CHemical libraries • Natural products • Combinatorial cHemistry • Structure-based design • In silico screening High throughput screening Resistance to an#viral drugs • Resistance to any anMviral drug must be anMcipated - Viruses replicate efficiently - Modest to HigH mutaMon frequencies • Special concern during extended therapy for cHronic infecMons (HIV, HBV, HCV) • Viral mutants resistant to every anMviral drug in arsenal Have been detected • DisconcerMng because anMviral arsenal is small Dangers of drug resistance • PaMent cannot be treated with same drug • If no other drug is available, infecMon cannot be stopped • GeneMc analysis of resistance provides insigHt into anMviral mecHanism • May reveal new strategies to reduce or circumvent problem Mechanisms of drug resistance • RNA viruses: error prone RNA polymerase, no correcMon mecHanism • One misincorporaon in 104 - 105 nucleodes polymerized (106 greater than Host DNA genome) • In RNA viral genome of 10 kb, this frequency leads to one mutaon in 1-10 genomes Mechanisms of drug resistance • DNA viruses: most DNA polymerases can excise and replace misincorporated nucleoMdes • DNA viruses evolve more slowly than RNA viruses because they Have less diversity Consider Acyclovir, the highly effec#ve, an#-herpes simplex virus drug – a prodrug; a nucleoside analog Many anMviral compounds are nucleoside and nucleoMde analogs Principles of Virology, ASM Press Acyclovir mechanism of ac#on Principles of Virology, ASM Press Improving acyclovir • Valacyclovir (valatrex), an L-valyl ester derivaMve of acyclovir, Has markedly improved bioavailability • Ester is taken up aier oral administraMon, acyclovir is released wHen the ester is cleaved by cellular enZymes Principles of Virology, ASM Press Acyclovir-resistant HSV • Arise spontaneously during virus replicaMon • Some mutants cannot pHospHorylate the pro-drug - Muta0ons are in viral thymidine kinase gene • Some mutants cannot incorporate pHospHorylated drug into DNA - Muta0ons are in viral DNA polymerase gene Acyclovir-resistant HSV • TK mutants can be devastaMng in AIDS paMents - May cause disseminated disease - OUen resistant to other nucleoside analogs that require viral TK (cross-resistance) - Treat with Foscarnet, DNA polymerase inhibitor (side effects) • DNA polymerase mutants may also be resistant to Foscarnet: no treatment opMons lei Symmetrel (amantadine) • Interacts with influenZa viral M2 protein (ion cHannel) • Blocks entry of protons into virion, prevents uncoaMng Principles of Virology, ASM Press Principles of Virology, ASM Press Influenza virus NA inhibitors Influenza virus NA inhibitors Zanamivir Oseltamivir • Designed to mimic natural ligand, sialic acid • Closer inHibitor to natural compound, less likely target can cHange to avoid binding drug wHile maintaining viable funcMon How inhibitors of NA (Tamiflu, Relenza) work Circula0ng H1N1 and H3N2 viruses are largely resistant to Adamantanes, not recommended for use H]p://www.cdc.gov/flu/weekly/index.Htm Inhibitors of picornavirus uncoa#ng PHarmac. THer. 29:287, 1985 WIN compounds Principles of Virology, ASM Press New HCV drugs Boceprevir Telaprevir Principles of Virology, ASM Press miRNA target: HCV H]p://www.nejm.org/doi/full/10.1056/NEJMoa1209026 HCV new drug pipeline hp://www.Hcvdrugs.com/ Targets for interven#on: HIV replica#on Principles of Virology, ASM Press The problem with AIDS therapy: relentless viral replica#on for years Azido-deoxythymidine (AZT) - first HIV drug • IniMally discovered during screens for anM-tumor cell compounds • PHospHorylated to acMve form by cellular kinases • CHain terminator • Not good substrate for most cellular polymerases, be]er for HIV RT Principles of Virology, ASM Press AZT • AZT Has substanMal side effects (unlike acyclovir) • Can be given orally, is absorbed rapidly, but Half-life is ~1 Hr (degraded by liver enZymes) • Consequently paMents dosed 2-3x daily • SHort Half-life, mulMple dose regimen problemaMc: resistant mutants will be selected Resistance to AZT • Mutants resistant to AZT arose immediately aier drug was licensed • Single aa cHanges at one of four sites in RT • Altered RT do not bind pHospHorylated AZT • New nucleoside analogs developed: Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T), Lamivudine (3TC) • THis lead to combinaMon therapy, use of two anMviral drugs to combat resistance • Mutants resistant to two drugs arose <1 yr Non-nucleoside RT inhibitors (NNRTI) nevirapine delavirdine efavirenz (Viramune) 11-cyclopropyl-4-methyl-5,11-dihydro-6H-
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