Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.
Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.
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The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication and for allowing the virus to evade the host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due to PLpro's restricted substrate binding pocket. In this report, we screened a 115 000-compound library for PLpro inhibitors and identified a new pharmacophore, based on a mercapto-pyrimidine fragment that is a reversible covalent inhibitor (RCI) of PLpro and inhibits viral replication in cells. Compound 5 had an IC50 of 5.1 μM for PLpro inhibition and hit optimization yielded a derivative with increased potency (IC50 0.85 μM, 6-fold higher). Activity based profiling of compound 5 demonstrated that it reacts with PLpro cysteines. We show here that compound 5 represents a new class of RCIs, which undergo an addition elimination reaction with cysteines in their target proteins. We further show that their reversibility is catalyzed by exogenous thiols and is dependent on the size of the incoming thiol. In contrast, traditional RCIs are all based upon the Michael addition reaction mechanism and their reversibility is base-catalyzed. We identify a new class of RCIs that introduces a more reactive warhead with a pronounced selectivity profile based on thiol ligand size. This could allow the expansion of RCI modality use towards a larger group of proteins important for human disease. Screening of the ChemDiv library against PLpro, an essential protein from the SCoV-2 virus, identified compound 5. Compound 5 is a reversible covalent inhibitor of PLpro and prevents SCoV-2 infection in cells.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
5.5
作者：
Kohnke B;Kutzner C;Grubmüller H
通讯作者：
Grubmüller H
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影响因子：
7.5
作者：
Jiang Y;Tong K;Yao R;Zhou Y;Lin H;Du L;Jin Y;Cao L;Tan J;Zhang XD;Guo D;Pan JA;Peng X
通讯作者：
Peng X
影响因子：
39.3
作者：
Lei, Sibei;Chen, Xiaohua;Wu, Jieping;Duan, Xingmei;Men, Ke
通讯作者：
Men, Ke
影响因子：
3.7
作者：
Armstrong LA;Lange SM;Dee Cesare V;Matthews SP;Nirujogi RS;Cole I;Hope A;Cunningham F;Toth R;Mukherjee R;Bojkova D;Gruber F;Gray D;Wyatt PG;Cinatl J;Dikic I;Davies P;Kulathu Y
通讯作者：
Kulathu Y