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  2. Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses

Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses

  • Eur J Med Chem. 2023 Mar 15;250:115186. doi: 10.1016/j.ejmech.2023.115186.
Lucile Brier 1 Haitham Hassan 1 Xavier Hanoulle 2 Valerie Landry 3 Danai Moschidi 2 Lowiese Desmarets 4 Yves Rouillé 4 Julie Dumont 3 Adrien Herledan 3 Sandrine Warenghem 3 Catherine Piveteau 1 Paul Carré 3 Sarah Ikherbane 3 François-Xavier Cantrelle 2 Elian Dupré 2 Jean Dubuisson 4 Sandrine Belouzard 4 Florence Leroux 5 Benoit Deprez 6 Julie Charton 7
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 CNRS, EMR9002 - BSI - Integrative Structural Biology, F-59000, Lille, France; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France.
  • 3 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France.
  • 4 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 5 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France.
  • 6 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France. Electronic address: benoit.deprez@univ-lille.fr.
  • 7 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France.
Abstract

Since end of 2019, the global and unprecedented outbreak caused by the coronavirus SARS-CoV-2 led to dramatic numbers of infections and deaths worldwide. SARS-CoV-2 produces two large viral polyproteins which are cleaved by two cysteine proteases encoded by the virus, the 3CL protease (3CLpro) and the papain-like protease, to generate non-structural proteins essential for the virus life cycle. Both proteases are recognized as promising drug targets for the development of anti-coronavirus chemotherapy. Aiming at identifying broad spectrum agents for the treatment of COVID-19 but also to fight emergent coronaviruses, we focused on 3CLpro that is well conserved within this viral family. Here we present a high-throughput screening of more than 89,000 small molecules that led to the identification of a new chemotype, potent inhibitor of the SARS-CoV-2 3CLpro. The mechanism of inhibition, the interaction with the protease using NMR and X-Ray, the specificity against host cysteine proteases and promising Antiviral properties in cells are reported.

Keywords

3CL protease Inhibitors; Antiviral; Coronavirus; SARS-CoV-2.

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