title: Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells.
abstract: New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses.
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Voss
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA, USA.
authors.forename: Moushimi
authors.initials: M
authors.lastname: Amaya
authors.affiliation: Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA, USA.
authors.forename: Claudius
authors.initials: C
authors.lastname: Mueller
authors.affiliation: Leidos Health Life Sciences, 5202 Presidents Court, Suite 110, Frederick, MD, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Roberts
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA, USA.
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn-Hall
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.affiliation: Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA, USA.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Petricoin
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA, USA. Electronic address: anaraya1@gmu.edu.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004663:Encephalitis Virus, Eastern Equine / Q000502:physiology; D004666:Encephalitis Virus, Venezuelan Equine / Q000502:physiology*; D004667:Encephalitis Virus, Western Equine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D020032:Tyrphostins; C069028:AG 127; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Ag-126; Alphavirus; ERK; Extracellular signal-regulated kinase; Kinase; MAPK