Antiviral Agents Upton D. Allen

Outline of Presentation Herpes group agents Anti-influenza agents Anti-hepatitis agents Anti-RSV Immune response modifiers Other From acyclovir to... Zanamivir…

Antiviral Agents for Herpes Viruses Acyclovir / Valacyclovir Ganciclovir / Valganciclovir Famciclovir / Penciclovir Cidofovir Foscarnet Trifluridine Vidarabine

Antivirals of Choice for Herpes Group Viruses HSV Acyclovir VZV Acyclovir EBVGanciclovir CMV Ganciclovir; Foscarnet HHV-6Foscarnet; Ganciclovir HHV-7Cidofovir HHV-8Cidofovir most potent

Antiviral Agents: Acyclovir, Valacyclovir, Famciclovir Valacyclovir is a prodrug of acyclovir; Oral bioavailability of acyclovir from valacyclovir is 54% as compared to 15-30% for acyclovir. Famciclovir is a prodrug for the active metabolite penciclovir; mean oral bioavailability of penciclovir from famciclovir is 77%. Penciclovir and acyclovir are primarily eliminated unchanged by the kidneys and have mean half-lives of 2.5 hours.

Nucleoside analogs - Antimetabolites Aciclovir® Zovirax® Valtrex® Guanosine analog Activity: DNA Herpes viruses (Herpes simplex, varicella, CMV, Epstein Barr)

Mechanism of Action of Acyclovir

Acyclovir molecules enter cell Converted to acyclovir monophosphate by the HSV enzyme thymidine kinase (TK). Cellular enzymes result in active drug acyclovir triphosphate. Acyclovir triphosphate competes with 2- deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA polymerase, as well as acting as a chain terminator.

Trifluridine Trifluridine - fluorinated pyrimidine inhibits viral DNA synthesis same as acyclovir incorporates into viral and cellular DNA Uses: HSV-1 and HSV-2 (topically)

Vidarabine An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Effects: GI intolerance and myelosuppression

Antiviral Agents for Herpes Viruses Acyclovir / Valacyclovir Ganciclovir / Valganciclovir Famciclovir / Penciclovir Cidofovir Foscarnet Trifluridine Vidarabine

Cymevene® Valcyte® Converted to triphosphates Inhibitors of viral DNA polymerases

Extracellular Intracellular GCV GCV-MP GCV-DPGCV-TP Cellular Enzymes Inhibits Viral DNA Polymerase (UL54 encoded) Mechanism of Ganciclovir Resistance Viral Protein Kinase (UL97 encoded)

Foscarnet - 1  Inhibits DNA polymerase  Does not require activation by virally encoded nucleoside kinases or phosphotransferases.

Foscarnet - 2 Foscarnet’s Selectivity  100-fold greater inhibitory effects against herpesvirus DNA polymerase compared with cellular DNA polymerase

Foscarnet - Toxicity  Renal  Significant magnesium wasting  CNS (tremor or seizures) notably in patients receiving calcineurin inhibitors.

Cidofovir -1  Nucleotide analog requires cellular phosphotransferases for activation  Does not require activation by virally encoded thymidine kinase or phosphotransferase

Cidofovir -2  Cidofovir-resistant isolates in vitro are cross- resistant to ganciclovir but generally susceptible to foscarnet.  Cidofovir is active against some, but not all CMV isolates that are resistant to foscarnet

Cidofovir — Toxicity  Contraindicated in patients with renal impairment  Contraindicated in patients receiving other nephrotoxic agents  Usually administered with probenecid and hydration to reduce nephrotoxicity

Leflunomide  Immunosuppressive agent used in treatment of rheumatoid arthritis.  Inhibits CMV by impairing late stages of viral assembly.  Has been used in some reports of ganciclovir or foscarnet resistant CMV.

Valganciclovir

Ganciclovir Time Profiles in HIV Patients 90% plasma GCV Excreted unchanged In urine; half-life 2-6 hours

Valganciclovir  Role in CMV prophylaxis  Effective in treating CMV retinitis in AIDS patients.  Emerging data in CMV treatment in transplantation.  Limited data in children  Caution in liver transplant recipients

Anti-Hepatitis Agents Lamivudine - Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir - Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin

Interferons Interferon Alfa Endogenous proteins induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA Bind to membrane receptors on cell surface May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release

Interferons Pegylated interferon Alfa A linear or branched polyethylene gylcol (PEG) moiety is attached to covalently to interferon Increased half-life and steady drug concentrations Less frequent dosing Tx chronic hepatitis C in combination with ribavirin

Ribavirin A guanosine analog Phosphorylated intracellularly by host enzymes Inhibits capping of viral messenger RNA Inhibits the viral RNA-dependent RNA polymerase Inhibits replication of DNA and RNA viruses

Drugs Used to Treat Hepatitis

Anti-Influenza Agents Amantadine Rimantadine Zanamivir Oseltamivir Peramivir Laninamvir Other

Amantadine and Rimantadine Cyclic amines Inhibit the uncoating of viral RNA therefore inhibiting replication Resistance due to mutations in the RNA sequence coding for the structural M2 protein Used in the prevention and treatment of Influenza A

Zanamivir and Oseltamivir Influenza neuraminidase cleaves terminal sialic acid residues from carbohydrates moieties in the surface of infected cells; destroys receptors recognized by viral hemaglutinin on cells, on newly released virions and on respiratory tract mucins. Cleaving of sialic acid essential for release of virus from infected cells and for spread with resp tract. Neuraminidase inhibitors limit spread of virus with resp tract; may prevent virus penetration as well.

Zanamivir and Oseltamivir Inhibits the enzyme neuraminidase Inhibit the replication of influenza A and Influenza B Treats uncomplicated influenza infections Zanamivir administered by oral inhalation Oseltamivir administered orally Resistance due to mutations in HA or NA genes. Mutations conferring resistance of oseltamivir do not necessarily lead to cross-resistance with zanamivir.

Mechanism of Action of Neuraminidase Inhibitors Influenza neuraminidase releases newly formed viruses from infected cells, allowing cell to cell spread. Neuraminidase inhibitors mimic the natural substrate of the influenza neuraminidase (the sialic acid receptors) and bind to the active site, preventing neuraminidase from cleaving host-cell receptors and releasing virus.

Zanamivir and Oseltamivir

≈ S N 1 ≈ TS ‡ Zanamivir Oseltamivir

Imiqumod (R-837, S-3608) 1-(2-methylpropyl)-1H- imidazo-[4,5-C] quinolin-4- amine Interferon inducer Immune-response modifer

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