2. Academic Validation
  3. A new chemotype that opens the S2∗ pocket of the 3CL protease exhibits antiviral activity against SARS-CoV-2

A new chemotype that opens the S2∗ pocket of the 3CL protease exhibits antiviral activity against SARS-CoV-2

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118277. doi: 10.1016/j.ejmech.2025.118277.
Laura Mourot 1,  Fatima-Zahra Chaibi 1,  Nour Bou-Karroum 1,  Paul Carré 1,  Alberto Abengozar Munoz 1,  Valérie Landry 2,  Audrey Tarricone 3,  Alexandre Biela 1,  Catherine Piveteau 1,  Gleb Novikov 1,  Elian Dupré 4,  Jean Dubuisson 5,  Sandrine Belouzard 3,  Florence Leroux 6,  Benoit Deprez 7,  Xavier Hanoulle 4,  Julie Charton 8
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 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.
  • 3 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France; 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.
  • 4 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.
  • 5 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.
  • 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.
  • 7 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.
  • 8 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France.
PMID: 41166766 DOI: 10.1016/j.ejmech.2025.118277
Abstract

Coronaviruses have caused 3 pandemics in the past 2 decades. The SARS-CoV-2, the causative agent of the COVID-19 already led to more than 7 million deaths worldwide. The 3CL protease (3CLpro, Mpro) plays a key role in the replication of the SARS-CoV-2 and has been validated as promising therapeutic target as evidenced by the recent clinical use of anti-coronavirus drugs inhibitors of this protease. In addition, its high conservation among coronaviruses gives an opportunity to identify broad-spectrum anti-coronavirus compounds to combat not only SARS-CoV-2 but also emerging coronaviruses. Here we report our efforts to optimize a small non-covalent inhibitor (F01) identified by an NMR-based screening, which resulted in a 40-fold potency improvement in 3CLpro inhibition with the low micromolar inhibitor 55. This compound displayed a promising Antiviral activity in cells without cytotoxicity. In addition, it was shown to inhibit the 3CLpro of SARS-CoV-1 and displayed high selectivity towards host cysteine proteases such as cathepsins L and K and calpain. The binding mode of a closed analog (57) was elucidated by X-ray structure with the protease and revealed the compound opens and fills a new pocket (S2∗) untargeted by Others inhibitors. This original structural feature along with the promising preliminary results obtained for this new chemotype deserve future optimization to further improve potency and pharmacokinetics properties of this series.

Keywords

3CL(pro); Non-covalent inhibitors; SARS-CoV-2.

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