TY - JOUR
T1 - TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate
AU - Komazin-Meredith, Gloria
AU - Cardinale, Steven C.
AU - Comeau, Katelyn
AU - Magalhaes, Kevin J.
AU - Hartline, Caroll B.
AU - Williams, John D.
AU - Opperman, Timothy J.
AU - Prichard, Mark N.
AU - Bowlin, Terry L.
N1 - Funding Information:
We are thankful to Karin M. Green for help with LC–MS/MS analysis. These studies were funded with Federal funds from the National Institutes of Allergy and Infectious Diseases under R44 AI 082799 .
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Abstract 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.
AB - Abstract 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.
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U2 - 10.1016/j.antiviral.2015.04.001
DO - 10.1016/j.antiviral.2015.04.001
M3 - Article
C2 - 25857706
AN - SCOPUS:84928487155
SN - 0166-3542
VL - 119
SP - 23
EP - 27
JO - Antiviral Research
JF - Antiviral Research
M1 - 3613
ER -