antiviral chemotherapy discovery of antiviral drugs targets of antiviral drugs

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Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

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Page 1: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Antiviral Chemotherapy

Discovery of antiviral drugsDiscovery of antiviral drugs

Targets of antiviral drugsTargets of antiviral drugs

Page 2: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

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).

Antiviral Chemotherapy

Page 3: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

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).

Antiviral Chemotherapy

Page 4: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

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

Antiviral Chemotherapy

Page 5: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Targeting drugs to specific steps of virus infection

Fig. 32.1 Inhibitors useful at different stages in virus replication cycle.

Antiviral Chemotherapy

Page 6: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Capsid-binding drugs prevent attachment and entry of virions

Antiviral Chemotherapy

Page 7: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Amantadine blocks ion channels and inhibits uncoating of influenza virions

Fig. 32.3 Proposed mechanism of action of amantadine on influenza virus uncoating.

Antiviral Chemotherapy

(a) Stucture of amantadine. (b) Structure of influenza virus

particle(c) 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.

Page 8: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Nucleoside analogues target viral DNA polymerases

Fig. 32.4 Structures of selected nucleosides and nucleoside analogues.

Antiviral Chemotherapy

Page 9: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Acyclovir is selectively phosphorylated by herpesvirus thymidine kinases

Fig. 32.5 Phosphorylation of acyclovir.

Antiviral Chemotherapy

Page 10: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Acyclovir is preferentially incorporated by herpesvirus DNA polymerases

Fig. 32.6 Mechanism of inhibition of herpes simplex virus DNA polymerase by acyclovir triphosphate.

Antiviral Chemotherapy

Page 11: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Cytomegalovirus encodes a protein kinase that phosphorylates ganciclovir

HIV-1 reverse transcriptase preferentially incorporates azidothymidine into DNA, leading to chain termination

Antiviral Chemotherapy

Page 12: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Fig. 32.7 Phosphorylation of azidothymidine.

Antiviral Chemotherapy

Page 13: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Nonnucleoside inhibitors selectively target viral replication enzymes

Fig. 32.8 Nevirapine, a nonnucleoside inhibitor of HIV-1 reverse transcriptase.

Antiviral Chemotherapy

Page 14: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

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.

Antiviral Chemotherapy

Page 15: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Neuraminidase inhibitors inhibit release and spread of influenza virus

Antiviral Chemotherapy

Page 16: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Antiviral chemotherapy shows promise for the future

Antiviral Chemotherapy

Page 17: Antiviral Chemotherapy Discovery of antiviral drugs Targets of antiviral drugs

Key Terms

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