Acyclovir is widely used in the treatment of herpesvirus infections, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). An overview of the mechanisms of action of and resistance to acyclovir and its major clinical uses will be provided here.
Dosing and treatment of the specific clinical syndromes are described in greater detail on the appropriate topic reviews.
Use of valacyclovir or famciclovir, which are later generation agents with a similar mechanism of action, are discussed elsewhere. (See "Valacyclovir: An overview" and "Famciclovir: An overview".)
MECHANISM OF ACTION
Acyclovir (9-[2-hydroxymethyl]guanine) is a nucleoside analog that selectively inhibits the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and varicella-zoster virus (VZV). After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase. This step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymes.
Acyclovir triphosphate competitively inhibits viral DNA polymerase by acting as an analog to deoxyguanosine triphosphate (dGTP). Incorporation of acyclovir triphosphate into DNA results in chain termination since the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides. Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio [1,2].