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Drug-Repurposing Screening Identified Tropifexor as a SARS-CoV-2 Papain-like Protease Inhibitor.
Ma, Chunlong; Hu, Yanmei; Wang, Yuyin; Choza, Juliana; Wang, Jun.
  • Ma C; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Hu Y; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Wang Y; Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • Choza J; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Wang J; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
ACS Infect Dis ; 8(5): 1022-1030, 2022 05 13.
Article in English | MEDLINE | ID: covidwho-1783938
ABSTRACT
The global COVID-19 pandemic underscores the dire need for effective antivirals. Encouraging progress has been made in developing small-molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the development of papain-like protease (PLpro) inhibitors faces several obstacles. Nevertheless, PLpro represents a high-profile drug target given its multifaceted roles in viral replication. PLpro is involved in not only the cleavage of viral polyprotein but also the modulation of host immune response. In this study, we conducted a drug-repurposing screening of PLpro against the MedChemExpress bioactive compound library and identified three hits, EACC, KY-226, and tropifexor, as potent PLpro inhibitors with IC50 values ranging from 3.39 to 8.28 µM. The three hits showed dose-dependent binding to PLpro in the thermal shift assay. In addition, tropifexor inhibited the cellular PLpro activity in the FlipGFP assay with an IC50 of 10.6 µM. Gratifyingly, tropifexor showed antiviral activity against SARS-CoV-2 in Calu-3 cells at noncytotoxic concentrations. Overall, tropifexor represents a novel PLpro inhibitor that can be further developed as SARS-CoV-2 antivirals.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Benzothiazoles / Drug Repositioning / Coronavirus Papain-Like Proteases / SARS-CoV-2 / Isoxazoles Limits: Humans Language: English Journal: ACS Infect Dis Year: 2022 Document Type: Article Affiliation country: Acsinfecdis.1c00629

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Benzothiazoles / Drug Repositioning / Coronavirus Papain-Like Proteases / SARS-CoV-2 / Isoxazoles Limits: Humans Language: English Journal: ACS Infect Dis Year: 2022 Document Type: Article Affiliation country: Acsinfecdis.1c00629