Anti-viral drugs

1. LECTURE 20: Anti-viral drugs Viro100: Virology 3 Credit hours NUST Centre of Virology & Immunology WaqasNasirChaudhry

2. Examples of anti-viral drugs • Nucleoside analogues • Ribavirin • Nucleoside analogues that inhibit herpesvirusDNA synthesis • Nucleoside analogues that inhibit reverse transcription • Non-nucleoside inhibitors of reverse transcription • HIV protease inhibitors • HIV fusion inhibitors • Influenza virus neuraminidase inhibitors

3. Nucleoside analogues • A number of anti-viral drugs are synthetic compounds structurally similar to nucleosides such as guanosine and 2-deoxythymidine and they act by interferingwith the synthesis of virus nucleic acids • After being taken into a cell a nucleoside analogue, like a nucleoside, is phosphorylated at the 5’ carbon (or its equivalent) to become a nucleotide analogue

4. The 5’ triphosphate derivative of the nucleoside analogue is the active form of the drug and acts as a competitive inhibitor of a viral polymerase such as a reverse transcriptase.

5. Mechanism of Action Nucleoside analogues • During nucleic acid synthesis, if one of these nucleotide analogues is incorporated into a growing strand, then nucleic acid synthesis is terminated. • The structure of the nucleotide analogue prevents it from accepting the next nucleotide. • In some cases the analogue lacks the hydroxyl group on the 3’ carbon (or lacks the 3’ carbon) necessary for the addition of the next nucleotide.

8. Nucleoside analogues that inhibitreverse transcription • Azidothymidine (AZT) is an analogue of thymidine. • It had been investigated as a possible anti-cancer drug and it was found to inhibit the reverse transcriptase of HIV. • Like other nucleoside analogues, it is phosphorylated to the 5’ triphosphate after uptake into a cell

9. AZT triphosphate binds more strongly to the viral reverse transcriptase than to the cell DNA polymerase, and the reverse transcriptase binds AZT triphosphate in preference to deoxythymidine triphosphate. • AZT thus inhibits HIV reverse transcription, but it can also interfere with cell DNA synthesis and, like ganciclovir, it can damage the bone marrow

10. Nucleoside analogues that inhibitherpesvirus DNA synthesis • Aciclovir strongly inhibits virus DNA synthesis but has very little effect on cell DNA synthesis. • In a herpesvirusinfected cell the first phosphorylation of acicloviris carried out by the virus thymidine kinase (TK). • The cell TK is produced only at certain stages of the cell cycle and it has a much lower affinity for aciclovir than the viral enzyme, so there is very little phosphorylation of aciclovirin uninfected cells.

11. During DNA synthesis, aciclovir triphosphate competes with deoxyguanosine triphosphate (dGTP) for incorporation into the new strand. • When aciclovir becomes incorporated, DNA synthesis is terminated due to the lack of a 3’ OH group. • Ganciclovir is more likely than aciclovir to become incorporated into cell DNA. • As a result ganciclovirhas a lower SI than aciclovir

12. Ribavirin • Ribavirin's carboxamide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. • For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine, inducing mutations in RNA-dependent replication in RNA viruses. • Such hypermutation can be lethal to RNA viruses • Still actual mechanism is unknown

13. HIV protease inhibitors • The maturation of a retrovirus virion involves the cleavage by a virus protease of the Gag and Gag – Pol proteins to form the virion proteins. • If this processing does not take place the virion does not acquire infectivity • Peptide mimics of the cleavage site in the protein have been developed and these compounds can fit into the active site of the HIV protease. • The result is that fewer virions bud from HIV-infected cells and those virions that do bud are non-infectious.

14. An example of an HIV protease inhibitor is ritonavir