Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine

Abstract

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).

Amino acid substitutions in the thymidine kinase gene of induced acyclovir-resistant herpes simplex virus type 1

“…One isolate (UKM-1) showed amino acid mutation (Gly34Lys) that has not yet been reported in any previous studies (TABLE (1), No. 1).…”

“…Mutation at TK gene in the UKM-3 and UKM-4 in which single amino acid substitution conferring ACV resistance mostly located in the ATP-binding site (amino acid: 51-63) were seen [3,[7][8]. There were 4 out of 5 samples (UKM-1, UKM-2, UKM-4 and UKM-5) contain two novel amino acid substitution at amino acid 32, which located outside the conserved region of the TK gene (TABLE (1), No. 1, 2, 4, 5).…”

“…Acyclovir (ACV) (currently marketed under the trade name such as Zovirax, Herpex, Cyclovir, Acivir, Zoral and Xovir) is a guanosine analogue antiviral drug which is primarily used for the treatment of herpes simplex virus infection [1]. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase and then further phosphorylated to acyclo-guanosine triphosphate (acyclo-GTP) by the cellular kinase.…”

Synthesis of the 5-phosphono-pent-2-en-1-yl nucleosides: A new class of antiviral acyclic nucleoside phosphonates

“…Compound 3 was protected (4, in 96% yield) and then treated with PPTS/methanol to give alcohol 5 in 78% yield. Compound 5 was converted to bromide 6 (99% yield), which underwent Arbuzov reaction in P(OEt) 3 to afford diethyl phosphonate 7 in 98% yield. Partial hydrogenation of 7 over Lindlar's catalyst 13 gave 8 with a cis double bond.…”

“…3 Valaciclovir, an oral prodrug of acyclovir, and famciclovir, an oral form of penciclovir, are now also available now as effective medications that can reduce the duration and severity of HSV-1 infections. 4 The general mode of action of nucleoside analogs is through inhibition of viral DNA polymerases by acting as competitive inhibitors and/or DNA chain terminators.…”