학술논문
A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication
Document Type
article
Author
Han, Hesong; Gracia, Albert Vallejo; Røise, Joachim J; Boike, Lydia; Leon, Kristoffer; Schulze-Gahmen, Ursula; Stentzel, Michael R; Bajaj, Teena; Chen, Dake; Li, I-Che; He, Maomao; Behrouzi, Kamyar; Khodabakhshi, Zahra; Nomura, Daniel K; Mofrad, Mohammad RK; Kumar, G Renuka; Ott, Melanie; Murthy, Niren
Source
RSC Advances. 13(16)
Subject
Language
Abstract
Covalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 have great potential as antivirals, but their non-specific reactivity with thiols has limited their development. In this report, we performed an 8000 molecule electrophile screen against PLpro and identified an α-chloro amide fragment, termed compound 1, which inhibited SARS-CoV-2 replication in cells, and also had low non-specific reactivity with thiols. Compound 1 covalently reacts with the active site cysteine of PLpro, and had an IC50 of 18 μM for PLpro inhibition. Compound 1 also had low non-specific reactivity with thiols and reacted with glutathione 1-2 orders of magnitude slower than other commonly used electrophilic warheads. Finally, compound 1 had low toxicity in cells and mice and has a molecular weight of only 247 daltons and consequently has great potential for further optimization. Collectively, these results demonstrate that compound 1 is a promising lead fragment for future PLpro drug discovery campaigns.