Identification of Quinolinones as Antivirals against Venezuelan Equine Encephalitis Virus.

Autor: Haese NN; Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA., May NA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA., Taft-Benz S; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., Moukha-Chafiq O; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Madadi N; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Zhang S; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Karyakarte SD; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Rodzinak KJ; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Nguyen TH; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Denton M; Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA., Streblow AD; Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA., Towers NA; High-Throughput Screening Center, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Rasmussen L; High-Throughput Screening Center, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Bostwick RJ; High-Throughput Screening Center, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Maddry JA; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Ananthan S; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Augelli-Szafran CE; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Suto MJ; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Sanders W; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., Moorman N; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., DeFilippis V; Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA., Heise MT; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., Pathak AK; Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama, USA., Streblow DN; Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA., Morrison TE; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 Aug 17; Vol. 65 (9), pp. e0024421. Date of Electronic Publication: 2021 Aug 17.
DOI: 10.1128/AAC.00244-21
Abstrakt: 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.
Databáze: MEDLINE