Enzymatic phosphorylation of the antiherpetic agent 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine.
The antiherpetic agent 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine (iNDG) is phosphorylated by HSV1 thymidine kinase, and its phosphorylated products inhibit DNA polymerase activity. iNDG exists in two enantiomeric forms, each with a primary and a secondary hydroxyl; thus, a number of possibilities for preferential phosphorylation exist, which were explored in this study. HSV1 thymidine kinase phosphorylates the primary hydroxyl of both the R and the S isomers of iNDG. This was established by comparison with analogues in which either the primary or the secondary hydroxyl was replaced by fluorine or hydrogen and also by a study of the NMR spectrum of the monophosphate. GMP kinase phosphorylates the R and the S monophosphates to the respective diphosphates. Further phosphorylation, however, is much more efficient with the S than with the R isomer. Furthermore, (S)-iNDG triphosphate is a more potent inhibitor of HSV1 DNA polymerase than (R)-iNDG triphosphate. These differences in the biochemical specificities of the two isomers account for the observed higher antiviral potency of (S)-iNDG as compared to that of (R)-iNDG.
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism*; D015774:Ganciclovir / Q000031:analogs & derivatives*; D051528:Guanylate Kinases; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D019384:Nucleic Acid Synthesis Inhibitors; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects*; D013237:Stereoisomerism; D013937:Thymidine Kinase / Q000378:metabolism
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D015774:Ganciclovir; D000212:Acyclovir