A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication.
RSC Adv
; 13(16): 10636-10641, 2023 Apr 03.
Article
in En
| MEDLINE
| ID: mdl-37025664
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
RSC Adv
Year:
2023
Document type:
Article