Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication

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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.

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