Antiviral Chemotherapy

1. Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

2. Antiviral Chemotherapy • Discovery of antiviral drugs • “Serendipity”—trying out compounds used for other purposes (amantadine and acyclovir). • Chemical modification of known active compounds (ganciclovir and azidothymidine). • High throughput screening assays of many compounds (nevirapine). • Rational design, often with the aid of three-dimensional structures of viral proteins (ritonavir and zanamivir).

3. Antiviral Chemotherapy • Targets of antiviral drugs • Capsid-binding drugs: picornavirus capsid proteins (attachment/entry). • Uncoating inhibitors: influenza M2 ion channel (uncoating). • Nucleoside analogues: viral DNA and RNA polymerases (genome replication): • May be selectively phosphorylated by virus-encoded kinases • Selectively inhibit viral DNA polymerases • Protease inhibitors: HIV-1 protease (virion maturation). • Neuraminidase inhibitors: influenza neuraminidase (virion release).

4. Antiviral Chemotherapy • The discovery and widespread use of antiviral compounds began only recently • Importance of antiviral drugs for basic science • How are antiviral drugs obtained? • cell-based high throughput screen • target-based high throughput screen

5. Antiviral Chemotherapy • Targeting drugs to specific steps of virus infection Fig. 32.1 Inhibitors useful at different stages in virus replication cycle.

6. Antiviral Chemotherapy • Capsid-binding drugs prevent attachment and entry of virions

7. Antiviral Chemotherapy • Amantadine blocks ion channels and inhibits uncoating of influenza virions • Stucture of amantadine. • Structure of influenza virus particle • Influenza virions in endosomes undergo fusion with endosomal membrane upon drop in pH induced by an endosomal proton pump. The M2 protein allows hydrogen ions to enter virion, releasing the RNP from the matrix protein. Amantadine blocks the M2 channel, inhibiting this process. Fig. 32.3 Proposed mechanism of action of amantadine on influenza virus uncoating.

8. Antiviral Chemotherapy • Nucleoside analogues target viral DNA polymerases Fig. 32.4 Structures of selected nucleosides and nucleoside analogues.

9. Antiviral Chemotherapy • Acyclovir is selectively phosphorylated by herpesvirus thymidine kinases Fig. 32.5 Phosphorylation of acyclovir.

10. Antiviral Chemotherapy • Acyclovir is preferentially incorporated by herpesvirus DNA polymerases Fig. 32.6 Mechanism of inhibition of herpes simplex virus DNA polymerase by acyclovir triphosphate.

11. Antiviral Chemotherapy • Cytomegalovirus encodes a protein kinase that phosphorylates ganciclovir • HIV-1 reverse transcriptase preferentially incorporates azidothymidine into DNA, leading to chain termination

12. Antiviral Chemotherapy Fig. 32.7 Phosphorylation of azidothymidine.

13. Antiviral Chemotherapy • Nonnucleoside inhibitors selectively target viral replication enzymes Fig. 32.8 Nevirapine, a nonnucleoside inhibitor of HIV-1 reverse transcriptase.

14. Antiviral Chemotherapy • Protease inhibitors can interfere with virus assembly and maturation • Ritonavir: a successful protease inhibitor of HIV-1 that was developed by rational methods Fig. 32.9 Steps in the development of ritonavir.

15. Antiviral Chemotherapy • Neuraminidase inhibitors inhibit release and spread of influenza virus

16. Antiviral Chemotherapy • Antiviral chemotherapy shows promise for the future

17. Acyclic Acyclovir Amantadine Azidothymidine Capsid-binding drugs Cell-based high throughput screen Enfuvirtide Ganciclovir Gangliosides Interferon Neuraminidase Nevirapine Nonnucleoside inhibitors Nucleoside diphosphate kinase Oseltamivir Peptidomimetic Pharmacokinetics Pleconaril Rational drug discovery Ritonavir Sialic acid Target-based high throughput screen Therapeutic index Thymidine kinase Thymidylate kinase Zanamivir Key Terms