The effects of maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 proteinReportar como inadecuado




The effects of maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 protein - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Herpesviridae

, 1:4

Herpesviridae

Abstract

BackgroundThe UL97 protein kinase of human cytomegalovirus phosphorylates the antiviral drug ganciclovir and is the target of maribavir action. A detailed enzyme kinetic analysis of maribavir on the various enzymatic functions of wild type and ganciclovir resistant forms of UL97 is required.

MethodsWild type and site directed mutant forms of the human cytomegalovirus UL97 gene product were expressed using recombinant baculoviruses and the purified products used to assess the effects of maribavir on the ganciclovir GCV kinase and protein kinase PK activities.

ResultsMaribavir was a potent inhibitor of the autophosporylation of the wild type and all the major GCV resistant UL97 mutants analysed M460I, H520Q, A594V and L595F with a mean IC50 of 35 nM. The M460I mutation resulted in hypersensitivity to maribavir with an IC50 of 4.8 nM. A maribavir resistant mutant of UL97 L397R was functionally compromised as both a GCV kinase and a protein kinase ~ 10% of wild type levels. Enzyme kinetic experiments demonstrated that maribavir was a competitive inhibitor of ATP with a Ki of 10 nM.

DiscussionMaribavir is a potent competitive inhibitor of the UL97 protein kinase function and shows increased activity against the M460I GCV-resistant mutant which may impact on the management of GCV drug resistance in patients.

Electronic supplementary materialThe online version of this article doi:10.1186-2042-4280-1-4 contains supplementary material, which is available to authorized users.

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Autor: Claire D Shannon-Lowe - Vincent C Emery

Fuente: https://link.springer.com/







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