Journal
ANTIVIRAL RESEARCH
Volume 119, Issue -, Pages 23-27Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2015.04.001
Keywords
Mechanism of action; Monohydroxymethyl methylenecyclopropane nucleosides; Herpes simplex virus; TAOK3
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Funding
- Federal funds from the National Institutes of Allergy and Infectious Diseases [R44 AI 082799]
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Monohydroxymethyl methylenecyclopropane nucleosides (MCPNs) with ether or thioether substituents at the 6-position show promise as broad-spectrum herpes virus inhibitors. Their proposed mechanism of action involves sequential phosphorylation to a triphosphate, which can then inhibit viral DNA polymerase. The inhibition of herpes simplex virus (HSV) by these compounds is not dependent on the viral thymidine kinase (TK), which is known to phosphorylate acyclovir (ACV), a standard treatment for HSV infections. Previous studies on the mechanism of action of these compounds against human cytomegalovirus (HCMV) implicated a host kinase in addition to HCMV UL97 kinase in performing the initial phosphorylation. After first eliminating other candidate HSV-1 encoded kinases (UL13 and US3) as well as potential host nucleoside kinases, using activity-based fractionation, we have now identified the host serine-threonine protein kinase TAOK3 as the kinase responsible for transforming the representative monohydroxymethyl MCPN analog MBX 2168 to its monophosphate. (C) 2015 Elsevier B.V. All rights reserved.
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