Integration of Computational and Experimental Techniques for the Discovery of SARS-CoV-2 PLpro Covalent Inhibitors

15 September 2023, Version 1


Papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro or Mpro) are enzymes essential for the replication of SARS-CoV-2, the virus responsible for COVID-19. While 3CLpro has been the main target of many potential antivirals including nirmatrelvir (active ingredient of Paxlovid), PLpro has proven to be more difficult to target and only a handful of inhibitors have been disclosed. PLpro inhibitors would be highly valuable tools in the fight against COVID19 resistant strains 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 of 13 µM through fusion of GRL-0617 and VIR-251. 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.


Virtual Screening
Medicinal Chemistry

Supplementary materials

Supporting information
Structures identified by virtual screening, experimental data for synthesized molecules. Additional information in synthesis.


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