Cellular proteins with reactive cysteine thiols

Cellular proteins with reactive cysteine thiols, collectively known as the reactive cysteinome, represent a diverse group of proteins containing cysteine residues with uniquely high nucleophilicity (Backus et al., 2016, Nature). These reactive thiols are essential for various biological processes, including enzymatic catalysis in proteases and phosphatases, and the regulation of signaling pathways through redox-sensitive modifications (Weerapana et al., 2010, Nature). In drug development, these sites are exploited by covalent inhibitors that form irreversible bonds with the cysteine sulfur, providing high potency and a long duration of action (Singh et al., 2011, Nature Reviews Drug Discovery). Notable examples include Ibrutinib, which targets Bruton's tyrosine kinase, and Sotorasib, which targets the KRAS G12C mutant. Despite their therapeutic utility, targeting reactive cysteines requires high selectivity to avoid off-target interactions with the thousands of other cysteines in the proteome, which can lead to toxicity or immune-mediated adverse effects (Resnick et al., 2024, Journal of Medicinal Chemistry).

Other names

Reactive cysteinomeThiol-reactive proteomeRedox-sensitive proteinsCysteine-centered targetsNucleophilic cysteines

Covalent modification of the cysteine thiol group, typically via Michael addition or nucleophilic substitution, leading to irreversible or slowly reversible inhibition of protein function (Singh et al., 2011, Nature Reviews Drug Discovery).