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  3. 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.
PMID: 36796300 DOI: 10.1016/j.ejmech.2023.115186
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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