Of a series of nucleoside analogues synthesised, 9-(2-hydroxyethoxymethyl) guanine was found to have marked antiviral activity in animal models of herpes virus infections, associated with very low toxicity.
A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED50) = 0.1 ,uM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virusspecified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di-and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration 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 determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsAl).
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SummaryEighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as prodrugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugs than the corresponding D-or D,L-isomers, suggesting the involvement of a stereoselective transporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueous solutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.
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