A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication. Issue 16 (4th April 2023)

• Record Type: Journal Article
• Authors: 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 R. K.; Kumar, G. Renuka; Ott, Melanie; Murthy, Niren
• Is Part Of: RSC advances. Volume 13:Issue 16(2023)
• Page Start: 10636
• Page End: 10641
• Publication Date: 2023-04-04
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d3ra00426k
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Compound 1 is a covalent inhibitor of SARS-CoV-2 PLpro that inhibits viral replication and has low non-specific reactivity with thiols. 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.