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Antivirals

Antivirals. Lect 7,8 Sadia Anjum. Targets for Anti-viral therapy. 1. viral attachment to cell and fusion (fusion inhibitors). 2. protein translation in infected cells (interferon). 3. protein processing (specific protease inhibitors). DNA synthetic enzymes (reverse transcriptase

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Antivirals

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  1. Antivirals Lect7,8SadiaAnjum

  2. Targetsfor Anti-viral therapy 1. viral attachment to cell and fusion (fusion inhibitors) 2. protein translation in infected cells (interferon) 3. protein processing (specific protease inhibitors) DNA synthetic enzymes (reverse transcriptase inhibitors, DNA polymerase inhibitors) 5. DNA integrase 6. Immune system (effective vaccines, restore immune surveillance)

  3. Targetsfor Anti-viral therapy

  4. Interferons Interferons are glycoproteins that come in 3 varieties: ά(made in leukocytes) β(made in fibroblasts) γ(made in T cells) activated T cells produce g interferon to modulate the immune response induced by viral infection, IL1, IL2, TNF

  5. Cytokine signaling pathway

  6. Multiple Pathways of Interferon Action

  7. Clinical use of Interferon • alpha interferon FDA approved: • genital warts (papillomavirus) • note: resiquimod has also been shown to be effective • hepatitis B and C • Kaposi’s sarcoma (HSV VIII) • Toxicity • fever, fatigue, marrow suppression, depression, acute influenza like symptoms • about 10-20% discontinue therapy due to toxicity

  8. Hepatitis C • Chronic hepatitis C virus (HCV) infection affects 2.7 million people in the United States. • Cirrhosis of the liver resulting from chronic HCV infection is the leading reason for liver transplantation in the U.S. • Drug treatments such as interferon and ribavirin are not very effective • HCV protease inhibitors are a promising new class of antivirals for this disease • BILN 2061 (Boehringer) looked good but appears to have cardiovascular toxicity and is on hold • VX-950 (Vertex Pharmaceuticals) is now in phase II trials and looks promising

  9. Ribavirin • A guanosine analog • phosphorylatedintracellularly by host enzymes • inhibits capping of viral messenger RNA • inhibits the viral RNA-dependent RNA polymerase • inhibits replication of DNA and RNA viruses

  10. Ribavirin antiviral HCV/Dengue

  11. Telaprevir (VX-950) with peg-IFN looks promising in clinical trials

  12. Anti-influenza virus drugs • Amantadine, Rimantadine • cyclic amines • inhibit the uncoating of viral RNA therefore inhibiting replication • only active against influenza A • blocks the influenza M2 ion channel on endosomes and prevents passage of H+ ions required for acidification and viral uncoating • mild CNS effects • Zanamivir, Oseltamivir • active against both influenza A and B • inhibits influenza viral neuraminidase. • Neuraminidase must cleave terminal sialic acid residues on receptors recognized by viral hemagglutinin. • Without this cleavage, virus remains trapped on infected cells --no release of infectious particles • treats uncomplicated influenza infections • administered intranasally

  13. Anti-influenza

  14. Targets for treatment of HIV (anti-retroviral drugs

  15. Antiretroviral Agents 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3)Protease inhibitors

  16. Antivirals: Purine Nucleosides Agent Antiviral Activity guanines acyclovir HSV 1 & 2, VZV ganciclovir (DHPG) CMV retinitis and systemic CMV infection ribavirin (RTCD) Influenza types A and B, RSV, LV, HV adenosines didanosine (ddl) HIV vidarabine (Ara-A) HSV, herpes zoster

  17. Antivirals: Pyrimidine Nucleosides Agent Antiviral Activity cytosines lamivudine (3TC) HIV zalcitabine (ddC) HIV thymine idoxuridine (IDU) HSV stavudine (d4T) HIV trifluridine HSV zidovudine (AZT) HIV

  18. Zidovudine (AZT) RTaseinhibitor • A deoxythymidine analog • enters the cell via passive diffusion • must be converted to the triphosphate form by mammalian thymidinekinase • competitively inhibits deoxythymidinetriphosphate for the reverse transcriptase enzyme • causes chain termination

  19. Zidovudine (AZT) RTaseinhibitor • mechanism • selective reverse transcriptase inhibitor

  20. Mechanism of selective toxicity of AZT DNA synthesis AZT concentration (uM)

  21. Zidovudine • mechanism • selective reverse transcriptase inhibitor • pharmacokinetics: • orally active, penetrates CSF • toxicity: • bone marrow depression (anemia, leukopenia) • headache, nausea, myopathy, anorexia, fatigue • therapeutic effects: • increase CD4+ T cells partially restoring immune system • reverses AIDS dementia • resistance: major problem • RTase mutations

  22. Lamivudine (3TC) • similar to zidovudine • resistance develops quickly: selects for met184val mutation in RTase • lamivudine + zidovudine combination dramatically slows resistance development

  23. NNRTIs (non-nucleoside reverse transcriptase inhibitors) Nevirapine Delavirdine Efavirenz

  24. NNRTIs • Bind to site on viral reverse transcriptase, different from NRTIs • results in blockade of RNA and DNA dependent DNA polymerase activity • do not compete with nucleoside triphosphates • do not require phosphorylation • these drugs can not be given alone • Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery

  25. Protease Inhibitors • The protease enzyme cleaves precursor molecules to produce mature, infectious virions • these agents inhibit protease and prevent the spread of infection • These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia

  26. Indinavir and Ritonavir • Specific inhibitors of the HIV-1 protease enzyme • mediated by expression of multiple and variable protease amino acid substitutions • Side Effects:hyperbilirubinemia • Contraindications:inhibitor/substrate for CPY3A4, do not give with antifungal azoles • Saquinavir • A synthetic peptide-like substrate analog • inhibits HIV-1 protease • prevents cleavage of viral polyproteins

  27. CCR5 and CXCR4 antagonists • Vicriviroc (Schering): Oct, 2005 discontinued Phase II trial due to therapeutic failure in some pts • Aplaviroc(GlaxoSmithKline): Oct, 2005 Phase III trials halted due to hepatotoxicity • Pfizer still has a compound in trials

  28. Anti-viral drugs Anti-herpes virus agents • Acyclovir / Valacyclovir • Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trifluridine / Idoxuridine / Vidarabine

  29. Anti-viral drugs Mechanism of action of Acyclovir and congeners : All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. The analog inhibits viral DNA-polymerase Only actively replicating viruses are inhibited Acyclovir is thus selectively activated in cells infected with herpes virus. Uninfected cells do not phosphorylate acyclovir.

  30. Acyclovir • FDA approved in 1982 • structural analog of deoxyguanosine • mechanism of selective toxicity • phosphorylated by viral thymidine kinase (TK) • preferential incorporation by viral DNA polymerase • causes chain termination • ~20% oral bioavailability (valacyclovir is 3-5X better) • penetrates CSF • effective in treating • primary Herpes infections (genital, encephalitis, neonatal) • chronic Herpes (does not cure but can reduce recurrence)

  31. Acyclovirmechanism of action

  32. Resistance to acyclovir • chronic therapy with acyclovir, valacyclovir, famciclovir • mutations in viral TK gene • alter affinity for drug or just completely inactivate the gene • viral DNA polymerase mutations • reduce recognition of phosphorylated drug as substrate for DNA synthesis

  33. Ganciclovir • for CMV, varicella zoster (chicken pox/shingles) • similar to acyclovir • 6-9% oral bioavailability • penetrates CSF • more active than acyclovir against CMV • toxicity: bone marrow suppression, CNS (headaches, convulsion, psychosis) • some toxic effects seen in about 40% of pts

  34. Foscarnet • binds to pyrophosphate site of viral polymerase (also RTase) • 100 fold greater selective inhibitor or viral versus human polymerase • poor oral bioavailability • nephrotoxicity is high (~50%) but reversible • hypocalcemia and CNS toxicity is also significant (25% pts) • useful in acyclovir/ganciclovir resistant HSV or CMV

  35. Virus Diseases Drug(s) of choice Alternative drugs FLU A Influenza Amantadine Rimantadine RSV Pneumonia, bronchiolitis Ribavirin (aerosol) HSV Genital herpes Acyclovir Foscarnet Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine Encephalitis Acyclovir Neonatal HSV infection Acyclovir Vidarabine Herpes infections in immuno- compromised host Acyclovir Foscarnet

  36. VZV In normal host No therapy In immunocompro-mised host, or during pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HIV AIDS HIV antibody positive with CD4 count < 500/mm3 Zidovudine ± protease inhibitors Didanosine, Stavudine HBV HCV Hepatitis B, C Interferons

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