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dc.contributor.authorChen, Han
dc.contributor.authorLi, Chengwei
dc.contributor.authorZemlicka, Jiri
dc.contributor.authorGentry, Brian
dc.contributor.authorBowlin, Terry
dc.contributor.authorCoen, Donald
dc.date.accessioned2019-10-05T03:28:12Z
dc.date.issued2016
dc.identifier.citationChen, Han, Chengwei Li, Jiri Zemlicka, Brian G. Gentry, Terry L. Bowlin, and Donald M. Coen. 2016. “Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase.” Antimicrobial Agents and Chemotherapy 60 (7): 4176–82. https://doi.org/10.1128/aac.00449-16.
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41482986*
dc.description.abstractCyclopropavir (CPV) is a promising antiviral drug against human cytomegalovirus (HCMV). As with ganciclovir (GCV), the current standard for HCMV treatment, activation of CPV requires multiple steps of phosphorylation and is enantioselective. We hypothesized that the resulting CPV triphosphate (CPV-TP) would stereoselectively target HCMV DNA polymerase and terminate DNA synthesis. To test this hypothesis, we synthesized both enantiomers of CPV-TP [(+) and (-)] and investigated their action on HCMV polymerase. Both enantiomers inhibited HCMV polymerase competitively with dGTP, with (+)-CPV-TP exhibiting a more than 20-fold lower apparent K-i than (-)-CPV-TP. Moreover, (+)-CPV-TP was a more potent inhibitor than GCV-TP. (+)-CPV-TP also exhibited substantially lower apparent K-m and somewhat higher apparent k(cat) values than (-)-CPV-TP and GCV-TP for incorporation into DNA by the viral polymerase. As is the case for GCV-TP, both CPV-TP enantiomers behaved as nonobligate chain terminators, with the polymerase terminating DNA synthesis after incorporation of one additional nucleotide. These results elucidate how CPV-TP acts on HCMV DNA polymerase and help explain why CPV is more potent against HCMV replication than GCV.
dc.language.isoen_US
dc.publisherAmerican Society for Microbiology
dash.licenseLAA
dc.titlePotency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalAntimicrobial Agents and Chemotherapy
dash.depositing.authorCoen, Donald Mark::f1d1eb8434c5ee0d3e2fa13c1a313e4d::600
dc.date.available2019-10-05T03:28:12Z
dash.workflow.comments1Science Serial ID 15341
dc.identifier.doi10.1128/AAC.00449-16
dash.source.volume60;7
dash.source.page4176


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