The acyclovir legacy: its contribution to antiviral drug discovery

The discovery of acyclovir marked the beginning of an exciting era in antiviral research. Early studies on the novel mode of action explained the selectivity of the compound and the remarkably narrow spectrum of activity against a subset of the herpesviruses. Throughout the past decade many clinical trials have demonstrated the efficacy and safety of this drug. Furthermore, the development of resistance does not appear to be a significant issue in normal individuals. Acyclovir provided the stimulus for further work in the antiherpes area, and this has led to the recent discovery of an oral prodrug (256U87), which delivers higher levels of acyclovir by the oral route, and to the discovery of 882C87, a highly selective inhibitor of varicella zoster virus. The novel mode of action of acyclovir involves an extremely selective phosphorylation step carried out by the herpesvirus thymidine kinase. It has recently been shown with another nucleoside analogue, ganciclovir, active against human cytomegalovirus (HMCV), that activation can be carried out by other unrelated kinases (in this case the UL97 gene product). Studies of this type may lead to the development of further novel inhibitors.