Drug-Repurposing Screening Identified Tropifexor as a SARS-CoV‑2 Papain-like Protease Inhibitor

Chunlong Ma, Yanmei Hu, Yuyin Wang, Juliana Choza, Jun Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1022-1030
Number of pages9
JournalACS Infectious Diseases
Volume8
Issue number5
DOIs
StatePublished - May 13 2022

Keywords

  • GRL0617
  • PL
  • SARS-CoV-2
  • antiviral
  • papain-like protease
  • tropifexor

ASJC Scopus subject areas

  • Infectious Diseases

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