title: TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate.
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.
authors: Microbiotix, Inc., Worcester, MA, USA. Electronic address: gxk21@psu.edu.
authors: Gloria
authors: G
authors: Komazin-Meredith
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: Steven C
authors: SC
authors: Cardinale
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: Katelyn
authors: K
authors: Comeau
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: Kevin J
authors: KJ
authors: Magalhaes
authors: University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Caroll B
authors: CB
authors: Hartline
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: John D
authors: JD
authors: Williams
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: Timothy J
authors: TJ
authors: Opperman
authors: University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Mark N
authors: MN
authors: Prichard
authors: Microbiotix, Inc., Worcester, MA, USA.
authors: Terry L
authors: TL
authors: Bowlin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000378:metabolism* / Q000494:pharmacology; D004279:DNA, Viral / Q000378:metabolism; D005347:Fibroblasts; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D000099317:Hippo Kinases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D004279:DNA, Viral; D006147:Guanine; D017346:Protein Serine-Threonine Kinases; D014764:Viral Proteins; C000592663:MBX 2168; C109163:STK24 protein, human; D000099317:Hippo Kinases
keywords: Herpes simplex virus; Mechanism of action; Monohydroxymethyl methylenecyclopropane nucleosides; TAOK3