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
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
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
Targeting drugs to specific steps of virus infection Fig Inhibitors useful at different stages in virus replication cycle. Antiviral Chemotherapy
Capsid-binding drugs prevent attachment and entry of virions Antiviral Chemotherapy
Amantadine blocks ion channels and inhibits uncoating of influenza virions Fig 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.
Nucleoside analogues target viral DNA polymerases Fig Structures of selected nucleosides and nucleoside analogues. Antiviral Chemotherapy
Acyclovir is selectively phosphorylated by herpesvirus thymidine kinases Fig Phosphorylation of acyclovir. Antiviral Chemotherapy
Acyclovir is preferentially incorporated by herpesvirus DNA polymerases Fig Mechanism of inhibition of herpes simplex virus DNA polymerase by acyclovir triphosphate. Antiviral Chemotherapy
Cytomegalovirus encodes a protein kinase that phosphorylates ganciclovir HIV-1 reverse transcriptase preferentially incorporates azidothymidine into DNA, leading to chain termination Antiviral Chemotherapy
Fig Phosphorylation of azidothymidine. Antiviral Chemotherapy
Nonnucleoside inhibitors selectively target viral replication enzymes Fig Nevirapine, a nonnucleoside inhibitor of HIV-1 reverse transcriptase. 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 Steps in the development of ritonavir. Antiviral Chemotherapy
Neuraminidase inhibitors inhibit release and spread of influenza virus Antiviral Chemotherapy
Antiviral chemotherapy shows promise for the future Antiviral Chemotherapy
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