Antiviral Agents Lecture PDF

Antiviral agents Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Most antiviral agents affect some host cell function. Effective agents usually target a viral protein. Antivirals: Amino acid substitutions in viral proteins by m...

Antiviral agents Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Most antiviral agents affect some host cell function. Effective agents usually target a viral protein. Antivirals: Amino acid substitutions in viral proteins by mutations render viruses, resistance to drugs. Points to Current agents inhibit replication, and upon withdrawal of drug replication may continue. ponder Therefore, effective host cell immunity is necessary for recovery. Current agents do not eliminate non- replicating or latent virus although some drugs have been shown to be effective (Eg: recent Hep C cure) Many drugs have to undergo terse phosphorylation to be effective. In-vitro test results for newer agents (all parameters) may not be indication for in-vivo effects.  Biological basis of viral resistance Drug resistance is reduced susceptibility to a drug and is expressed as an altered IC50 or IC90 (drug concentration required to inhibit viral growth by 50% or 90% respectively). Specific mutations in the viral genome, which leads to alterations in the viral target protein (for example, HIV reverse transcriptase) or the viral drug activator (for example, herpes simplex thymidine kinase). Error rate of viral polymerases, especially for RNA viruses such as HIV and influenza, which replicate the viral genome is very high. A wide range of viral variants, including those with mutations associated with drug resistance, will therefore be present. In some cases, multiple mutations are required for the development of high-level resistance, and insufficient suppression of viral replication by antiviral drugs will predispose to their sequential acquisition. Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113839/ Why do drugs have to undergo phosphorylation to be effective? Sothey canbe integrated into Out Madurry  Idoxuridine (Herplex, Ophthalmic), Vidarabine (vye-DARE-a-been, Ara-A, adenine arabinoside, not in the US), Anti-herpetic analog Trifluridine (TFT, trifluorothymidine, and anti-CMV ophthalmic, Viroptic), agents Acyclovir (ACV, Acycloguanosine, Zovirax, useful for varicella VZV), Valacyclovir, Ganciclovir (GCV, DHPG), Valganciclovir (Valcyte), Penciclovir, Famciclovir (FCV, Foscavir), Foscarnet (PFA, phosphonoformate), Cidofovir (useful for CMV, Vistide), Fomivirsen (useful for CMV retinitis, Thigh Vitravene, currently not in US) etc.  How do DNA or RNA base ‘analogues’ work as drugs to prevent replication?  Influenza Amantadine (Symmetrel, Symadine), Influenza & RSV Rimantadine (Flumadine) Nolongerused drugs (H & N?) Zanamivir (Relenza) & Oseltamivir (Tamiflu), Peramivir (Rapivab) Baloxavir marboxil (Xofluza) Respiratory Syncytial virus Ribavirin (Virazole, Copegus, Rebetol, also used in hepatitis C), Palivizumab (pal-i-VIZ-u-mab, Synagis) monoclonal antibodies  Baricitinib (Olumiant) COVID-19 Drugs Remdesivir (Veklury) Toclizumab (Actemra) Nirmatrelvir/Ritonavir (Paxlovid) INVESTIGATIONAL USE Maybe seen exam on Nonspecific antiviral agents Interferon alpha (lymphoblastoid) & Interferon beta (fibroblast): Intron A, Roferon A, Alferon N, Wellferon, Avonex, Betaseron, Rebetron etc. RC Gallo: HTLV III = HIV L Montagnier : LAV= HIV Gallo’s NSU Visit 2022  NRTIs (nucleoside reverse transcriptase inhibitors): Zidovudine (Azidothymidine, AZT, Zidovudine, ZDV), Didanosine (ddI, Videx), Zalcitabine (ddC, Hivid), Stavudine (d4T, Zerit), Abacavir (Ziagen), Lamivudine (Epivir), Adefovir (Preveon HIV-not currently used, Hepsera – for Hep B infections), Anti-retroviral Emtricitabine (Emtriva), Abacavir plus lamivudine plus zidovudine (Trizivir) agents (6 NNRTIs (nonnucleoside reverse transcriptase classes, about 30 inhibitors): Nevirapine (Viramune), Delavirdine (Rescriptor), Efavirenz (eh-FAV-er-enz, Sustiva), drugs): Etravirine (Intelence), Rilpivirine (Edurant) LessResistance of Manycombinations HIV Protease inhibitors: Indinavir (Crixivan), Drugsused treatment in Ritonavir (Norvir), Saquinavir (Invirase, Fortovase), Lopinavir (with ritonavir as Kaletra), Nelfinavir (Viracept), Amprenavir (Agenerase), Atazanavir (AT-az-an-a-veer, Reyataz), Darunavir (Prezista) Fosamprenavir (Lexiva, pediatric in 2007), Tipranavir (non-peptide PI, Aptivus) etc. of Inhibitmaturation virus att lengthen a É avir isendingforall  Is reverse transcriptase (RT) a DNA polymerase enzyme? kinda RNA DNAPot Dependent Difference between NRTIs Activesite and NNRTIs?cosite ThesiteofEnzymaticbinding nonactivesite Difference between NRTIs & NtRTIs? mucleosides lacks phosphatgroup hasaphosphate  HIV Entry, Fusion and Integration Inhibitors: HIV……….. Enfuvirtide (en-FEW-ver-tide, Fuzeon): A 33 aa peptide that binds to GP41 and tf reo prevents binding or fusion of HIV to cellular membrane Entry inhibitor: Maraviroc (Selzentry): CCR5 co-receptor binding prevents entry of the virus in the host cell. rosii.ie Integrase Strand transfer inhibitor: Raltegravir (Isentress), Dolutegravir (Tivicay) & Elvitegravir (Vitekta, in combination as Stribild): Prevents provirus integration into the host DNA. Ice  Emtricitabine, Tenofovir (Truvada, Descovy) HIV PrEP Emtricitabine: Emtricitabine is a synthetic nucleoside analog of cytidine. Emtricitabine 5'- triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) Tenofovir disoproxil fumarate: Tenofovir See inhibits viral reverse transcriptase and acts as a DNA chain terminator.  A patient with nosocomial needle prick injury as a risk factor for HIV infection: Which drug would be best to prevent latent forms of virus (viral genomes present in the cell)?  Family Hepadnaviridae: Hepatitis B (HBV) drugs: NRTIs: Telbivudine (Tyzeka), Lamivudine (Epivir), Entecavir (Baraclude), Adefovir (Hepsera), Vidarabine HBV, HPV & HCV (discontinued in the US), Tenofovir, Interferons DRUGS Papovaviridae: ONA S HPV: Imiquimod (Aldara): Immune response modifier. Gardasil 9 is a nano-valent HPV vaccine. Family Flaviviridae: Hepatitis C (HCV) drugs: Boceprevir (Victrelis) & Telaprevir (Incivek, Incivo), Simeprevir (Olysio): NS3-4a protease inhibitors (protease that cleaves 3000aa polyprotein to about 10 proteins in HCV), NS5A protein super- phosphorylation inhibitors and NS5B polymerase inhibitors first cured Disease viral  Why RT drugs are useful for HBV,-a DNA virus? Strange HCV, an RNA virus, does it need to make DNA in host cells for replication? RNA If not, what is the enzyme that is used by HCV to do its replication? RNA Depe RNAPOL HSV I & HSV II HSV 1 and HSV 2: HSV1: diseases of mouth, face skin esophagus or brain HSV2: diseases of genitals, rectum, skin, hands and meninges  Acyclovir: An acyclic guanine nucleoside analogue. Congeners are Famciclovir, Penciclovir, Valacyclovir etc. Mechanism: Inhibits viral DNA polymerase. Uses viral and cellular kinases for activation of the drug. Clinical uses: Herpes Simplex virus Type I and Type II. In immune compromised patients initial infections are controlled greater than recurrent infections. In HSV encephalitis it has shown to reduce mortality by 50%. Adverse:Transient renal dysfunction. Idoxuridine and Trifluridine Mechanism: Inhibits various enzyme systems including DNA synthesis. Breaks DNA strands and causes mistakes during transcription. Clinical Uses: Approved for Topical treatment of herpes simplex I keratitis. Also used in ocular epithelial HSV infections. Anti- Trifluridine is also approved for primary keratoconjunctivitis. Trifluridine is tenfold potent for herpes keratitis than Idoxuridine. herpetic Vidarabine (topical in the US, Adenosine arabinoside, Ara-A) The first drug discovered to treat herpes infection. Mechanism: Analog of adenosine. Agents Metabolite inhibits DNA polymerase. Clinical uses: Approved I.V. for Herpes simplex encephalitis, neonatal herpes, I.V. herpes zoster or varicella in immune suppressed patients. ONAPO Foscarnet Mechanism: An inorganic pyrophosphate that interact directly and inhibits viral RNA polymerase, DNA polymerase and HIV RT. Resistance is by point mutations see Inhibitors serum polymerase. Use: intravenous foscarnet is approved for CMV retinitis in in the viral immunocompromised patients. Adverse: Nephrotoxicity, electrolyte disturbances (symptomatic hypocalcemia and concomitant administration of pentamidine increases risk) Ribavirin (for RSV as Virazole and with interferons as Rebetol or Rebetron) Ribavirin is a purine nucleoside analogue. Mechanism: Prevents capping of viral mRNA Use: Respiratory syncytial viral infections-bronchitis, pneumonia (as aerosol-Virazole). Ribavirin aerosol is approved in the US for RSV bronchiolitis and pneumonia in hospitalized children.  ANTIRETROVIRAL AGENTS NRTIs, Competitive inhibition, competes with triphosphate biding sites : Azidothymidine, Zidovudine (AZT) class: Didanosine (ddI), Zalcitabine (ddC), Lamivudine (3TC), Stavudine (d4T), Emtricitabine (Emtriva) are other RT inhibitors. Tenofovir and Adefovir (they are NRTIs sometimes called NtRTIs). Drug Activation non-selective and occurs in infected as well as uninfected cells. Mechanism: Base analogues. Initially phosphorylated by cellular thymidine kinase. Zidovudine triphosphate terminates viral DNA synthesis by reverse transcriptase (RT). Common Use: HIV infection with CD4