Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2

Science. 2021 Aug 20;373(6557):931-936. doi: 10.1126/science.abg5827. Epub 2021 Jul 20.

Abstract

There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Benzamides
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Catalytic Domain
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / chemistry
  • Coronavirus 3C Proteases / metabolism
  • Coronavirus OC43, Human / drug effects*
  • Coronavirus OC43, Human / physiology
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, Transgenic
  • Microbial Sensitivity Tests
  • Piperidines
  • Pyridines
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • SARS-CoV-2 / physiology
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use
  • Viral Load / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Benzamides
  • Cysteine Proteinase Inhibitors
  • Piperidines
  • Pyridines
  • Thiazoles
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
  • masitinib