antiviral chemotherapy

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).


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).


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


Targeting drugs to specific steps of virus infection

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


Capsid-binding drugs prevent attachment and entry of virions


Amantadine blocks ion channels and inhibits uncoating of influenza virions

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


(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. 32.4 Structures of selected nucleosides and nucleoside analogues.


Acyclovir is selectively phosphorylated by herpesvirus thymidine kinases

Fig. 32.5 Phosphorylation of acyclovir.


Acyclovir is preferentially incorporated by herpesvirus DNA polymerases

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


Cytomegalovirus encodes a protein kinase that phosphorylates ganciclovir

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


Fig. 32.7 Phosphorylation of azidothymidine.


Nonnucleoside inhibitors selectively target viral replication enzymes

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


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.


Neuraminidase inhibitors inhibit release and spread of influenza virus


Antiviral chemotherapy shows promise for the future


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

antiviral chemotherapy

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