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.
Huang et al. (Wed,) studied this question.