Week 10 Antiviral Viruses obligate intracellular microorganisms Utilize

Week 10 Antiviral

• Viruses - obligate intracellular microorganisms • Utilize- host metabolic enzymes and ribosomes for protein synthesis • Drugs for viruses must penetrate host cells. • Might negatively impact normal pathways of the host • Narrow therapeutic index compared to antibacterials

• Interfere with • • viral nucleic acid synthesis Regulation viral cell binding- attachment/penetration (antiviral antibodies-gamma globulin) virus uncoating (interferon, amantadine, rimantadine) metabolic pathways Early translation-fomivirsen Transcription- inhibitors of DNA polymerase, Inhibitors of RNA dependent DNA polymerase • nucleic acid analogs - RNA and DNA production. • Inhibition of single steps in the viral replication – virustatic (temporary)- needs host immune response.

• Nucleoside reverse transcriptase inhibitors (NRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Protease inhibitors (PIs) • Integrase inhibitors (INSTIs) • Fusion inhibitors (FIs) • Chemokine receptor antagonists (CCR 5 antagonists)

Nucleoside reverse transcriptase inhibitors(NRTI) • Block reverse transcriptase • This enzyme reverse transcriptase to convert its RNA into DNA (reverse transcription) • HOW? Activated- phosphorylation to the triphosphate form by cellular enzymes- competes with cellular triphosphates, which are substrates for proviral DNA by viral reverse transcriptase.

NRTI • • • Entecavir Abacavir Tenofovir Adefovir Lamivudine Zidovudine Telbivudine Stavudine Emtricitabine Didanosine

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)- Non-nukes • Binding directly to the enzyme- at a site different from the nucleoside binding component- cause an allosteric inhibition of the transcriptase • Nevirapine • delavirdine • efavirenz

Protease inhibitors • Synthetic drugs - inhibit the action of HIV-1 protease (cleaves two precursor proteins into smaller fragments)- necessary for viral growth, infectivity and replication. • Bind to the active site of the protease enzyme - prevent the maturation of the newly produced virions – making them noninfectious.

Protease inhibitors • • • Boceprevir Simeprevir Fosamprenavir Lopinavir Darunavir Telaprevir Tipranavir Ritonavir Arazanavir Nelfinavir Indinavir Saquinavir

Integrase inhibitors (INIs) • Block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. • Dolutegravir • Elvitegravir • Raltegravir

Fusion inhibitors • Blocking cognate virus–receptor interactions is the most obvious antiviral paradigm for entry inhibitors- maraviroc- CC chemokine receptor 5 (CCR 5) • cholesterol and unsaturated phospholipids can increase and decrease membrane rigidity • maraviroc • enfuvirtide

CCR 5 inhibitors • Prevent- CD 4 T-cells by blocking the CCR 5 receptor- Maraviroc • • When the CCR 5 receptor is unavailable, tropic site cannot engage with a CD 4 T-cell to infect the cell. • Aplaviroc • Vicriviroc

Virus attachment to the host cell Virus entry Reverse transcription Integration of viral DNA into host genome • Anionic polymer • Chemokine receptor inhibito, CD 4 inhibitör, Enfuvirtide • NRTI • NNRTI • Integrase inhibitors Trasncription and translation Proteolytic processing of viral proteins Budding of new virüs particles • PIs

• Foot and Moth Disease • antiviral treatment in a vaccinated zone could protect against viral dissemination and fill the time gap between vaccination and the development of protective immunity. • ribavirin, ′ 2′-C-methylcytidine, pyrazinecarboxamide • Immunomodulators such as IFN • Acyclic nucleoside phosphonates- cidofovir • Feline herpesvirus 1 - Aciclovir, ganciclovir and penciclovir are acyclic nucleoside, recombinant feline IFN-ω • Feline retrovirus- IFN • Canine viral- feline IFN-ω is licensed for use in dogs with CPV-2 (canine parvoviral) clinical infection