Identification of quinolinones as antivirals against venezuelan equine Encephalitis virus

Nicole N. Haese, Nicholas A. May, Sharon Taft-Benz, Omar Moukha-Chafiq, Nikhil Madadi, Sixue Zhang, Shuklendu D. Karyakarte, Kevin J. Rodzinak, Theresa H. Nguyen, Michael Denton, Aaron D. Streblow, Nichole A. Towers, Lynn Rasmussen, Robert J. Bostwick, Joseph A. Maddry, Subramaniam Ananthan, Corinne E. Augelli-Szafran, Mark J. Suto, Wes Sanders, Nathaniel MoormanVictor DeFilippis, Mark T. Heise, Ashish K. Pathak, Daniel N. Streblow, Thomas E. Morrison

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.

Original languageEnglish (US)
Article numbere00244-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number9
DOIs
StatePublished - Sep 2021
Externally publishedYes

Keywords

  • Alphavirus
  • Antiviral agents

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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