Acyclovir: discovery, mechanism of action, and selectivity.

The reasons for acyclovir's activity and selectivity in cells infected with HSV or VZV may be summarized as follows: 1. Activation by a HSV- or VZV-specified TK. 2. Greater sensitivity of viral DNA polymerase than of the cellular polymerases to ACV-TP. 3. Inactivation of the viral DNA polymerase, but not the cellular polymerases, by ACV-TP. 4. Chain termination of viral DNA by incorporation of ACV-MP. For the Epstein-Barr virus, which is also sensitive to acyclovir, there is no selective activation in infected cells [Colby et al., 1981], but the viral polymerase can be inhibited by very low levels of ACV-TP [Datta et al., 1980]. For HCMV, the activation of acyclovir is very poor but the viral polymerase is also more sensitive to ACV-TP than the cellular polymerases. One of the important contributions of acyclovir was the demonstration for the first time that a compound could prevent the DNA replication of a DNA virus at concentrations far below those that affect cellular DNA synthesis. As we all know, in the past 15 years there has been a complete rejuvenation of antiviral chemotherapy. I think it is very fortunate that we changed our outlook on the possibility of making potent and selective antiviral agents in time so that, when the AIDS epidemic came along, we did not feel completely at a loss on ways to attack viral disease.