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  3. Integration of computational and experimental techniques for the discovery of PLpro covalent inhibitors. When large virtual screening and rational design meet

Integration of computational and experimental techniques for the discovery of PLpro covalent inhibitors. When large virtual screening and rational design meet

  • Eur J Med Chem. 2026 Apr 15:308:118698. doi: 10.1016/j.ejmech.2026.118698.
Ho Ying Huang 1,  Sharon Pinus 1,  Xiaocong Zhang 1,  Guanyu Wang 1,  Mathilde Broquière 2,  Richard Boulon 2,  Andrés M Rueda 1,  Yaouba Souaibou 1,  Solène Huck 1,  Mitchell Huot 1,  Danielle Vlaho 1,  Joshua Pottel 3,  Felipe A Venegas 1,  Zhuoqun Lu 1,  Christopher Hennecker 1,  Julia Stille 1,  Jevgenijs Tjutrins 1,  Caitlin E Miron 1,  Anne Labarre 1,  Jessica Plescia 1,  Mihai Burai-Patrascu 4,  Steven Laplante 2,  Laurent Chatel-Chaix 2,  Anthony K Mittermaier 5,  Nicolas Moitessier 6
Affiliations

Affiliations

  • 1 Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, H3A 0B8, Canada.
  • 2 Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, H7V 1B7, Canada.
  • 3 Molecular Forecaster 2075-910, Boul. Robert Bourassa, Montreal, QC, H3A 2L1, Canada.
  • 4 Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, H3A 0B8, Canada; Molecular Forecaster 2075-910, Boul. Robert Bourassa, Montreal, QC, H3A 2L1, Canada.
  • 5 Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, H3A 0B8, Canada. Electronic address: [email protected].
  • 6 Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, H3A 0B8, Canada; Molecular Forecaster 2075-910, Boul. Robert Bourassa, Montreal, QC, H3A 2L1, Canada. Electronic address: [email protected].
PMID: 41740581 DOI: 10.1016/j.ejmech.2026.118698
Abstract

Papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro or Mpro) are viral Enzymes essential for the replication of SARS-CoV-2, the virus causing coronavirus disease of 2019 (COVID-19) Infection. While 3CLpro has been the main target of many potential antivirals including nirmatrelvir (active ingredient of Paxlovid), PLpro has proven to be more challenging to target and only a handful of inhibitors have been disclosed. However, PLpro inhibitors would enrich the therapeutic arsenal against COVID-19 resistant strains to 3CLpro inhibitors and in future coronavirus pandemics. Combining our experience with 3CLpro covalent inhibitors with our expertise in structure-based covalent drug discovery, we rationally designed PLpro inhibitors achieving a maximum potency (IC50) of 13 μM through fusion of GRL0617 and VIR-251 PLpro inhibitors. In parallel, we launched an integrated large scale virtual screening/experimental approach, identifying four novel chemical series active at micromolar concentrations against PLpro. We report herein our investigations including rational design, virtual screening, synthesis of selected structures and in vitro assays leading to novel PLpro inhibitors. Surprisingly, these two very distinct approaches led to structures with similar features.

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