title: Inhibition of enterovirus VP4 myristoylation is a potential antiviral strategy for hand, foot and mouth disease.
abstract: The Hand, Foot and Mouth Disease (HFMD) can result from infections by a plethora of human enteroviruses of the species Enterovirus A and B. These infections are highly contagious, resulting in regular outbreaks especially in the Asia-Pacific Region in the recent decade. Although this disease is generally a childhood affliction which manifests as a mild, febrile illness accompanied by the vesicles on the hands, feet and mouth, permanent morbidity or even fatality can result from severe forms of the disease in a subset of the infected patients. The N-terminal myristoylation signal (MGXXXS) of viral capsid protein VP4, one of the four viral structural proteins, is an extremely well conserved feature of enteroviruses, a potential antiviral target that may yield broad-spectrum inhibitors of HFMD. In this study, we have confirmed through the use of small interfering RNAs, human N-myristoyltransferase 1 plays an integral role in human Enterovirus 71 replication. Subsequent studies by inhibition of myristoylation using different myristic acid analogues elicited differential effects on the virus replication in human rhabdomyosarcoma cells. In particular, 2-hydroxymyristic acid specifically inhibited the cleavage between VP4 and VP2, part of the virion maturation process required to ensure infectivity of progeny virions while 4-oxatetradecanoic acid reduced the synthesis of viral RNA. These findings suggest that the requirement of a myristate moiety in viral structural protein precursor cleavage can serve as a viable antiviral target for further research.
authors: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, Singapore 138673, Singapore.
authors: Yong Wah
authors: YW
authors: Tan
authors: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, Singapore 138673, Singapore.
authors: Wan Jin
authors: WJ
authors: Hong
authors: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, Singapore 138673, Singapore; Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, National University Health System, National University of Singapore, Singapore 117597, Singapore. Electronic address: jhchu@imcb.a-star.edu.sg.
authors: Justin Jang Hann
authors: JJ
authors: Chu
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D006232:Hand, Foot and Mouth Disease / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D009227:Myristic Acids / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D015678:Viral Structural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005230:Fatty Acids, Nonesterified; D009227:Myristic Acids; D015678:Viral Structural Proteins; C076272:4-oxatetradecanoic acid
keywords: Antiviral; EV71; HFMD; Human enterovirus; Myristoylation