Issue 16, 2023, Issue in Progress

A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication

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.

Graphical abstract: A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication

Supplementary files

Article information

Article type
Paper
Submitted
19 Jan 2023
Accepted
27 Feb 2023
First published
04 Apr 2023
This article is Open Access
Creative Commons BY license

RSC Adv., 2023,13, 10636-10641

A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication

H. Han, A. V. Gracia, J. J. Røise, L. Boike, K. Leon, U. Schulze-Gahmen, M. R. Stentzel, T. Bajaj, D. Chen, I.-Che Li, M. He, K. Behrouzi, Z. Khodabakhshi, D. K. Nomura, M. R. K. Mofrad, G. R. Kumar, M. Ott and N. Murthy, RSC Adv., 2023, 13, 10636 DOI: 10.1039/D3RA00426K

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