Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine (Reprinted from Proc. Natl Acad. Sci. USA, vol 74, pg 5716-5720, 1977)

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED50 = 0 .1 mu M] against herpes simplex virus type I. This acyclic nucleoside analo g, termed acycloguanosine, is converted to a monophosphate by a virus-speci fied pyrimidine deoxynucleoside (thymidine) kinase and is subsequently conv erted to acycloguanosine di- and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited e xtent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polym erase (DNA nucleotidyltransferase) 10-30 times more effectively than cellul ar (HeLa S3) DNA polymerase. These factors contribute to the drug's selecti vity: inhibition of growth of the host cell requires a 3000-fold greater co ncentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine. The identity of the kinase that phosphorylates acycloguanosine was determin ed after separation of the cellular and virus-specified thymidine kinase ac tivities by affinity chromatography, by reversal studies with thymidine, an d by the lack of monophosphate formation in a temperature-sensitive, thymid ine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsA1).