Intracellular cysteine-containing proteins

Intracellular cysteine-containing proteins represent a broad and diverse class of molecules defined by the presence of the amino acid cysteine, which contains a highly reactive nucleophilic thiol group (Nature Reviews Chemistry, 2017). These proteins perform critical biological roles, including acting as catalytic centers in proteases and oxidoreductases, stabilizing protein structures through disulfide bond formation, and facilitating metal ion coordination in structural motifs like zinc fingers (PubMed, 2001). In the context of pharmacology, these proteins are the primary targets for covalent inhibitors, which utilize electrophilic warheads to form stable chemical bonds with specific cysteine residues, thereby providing potent and sustained therapeutic effects (Nature Reviews Drug Discovery, 2016). However, because thousands of intracellular proteins contain accessible cysteines, a major challenge in drug design is achieving selectivity to avoid off-target reactivity (Journal of Medicinal Chemistry, 2015). Non-specific binding to this broad class of proteins can lead to cellular toxicity, depletion of the antioxidant glutathione, or the formation of drug-protein adducts that trigger immune responses (Toxicological Sciences, 2011). Dysregulation of the redox state of these proteins is implicated in various pathologies, including cancer, neurodegeneration, and inflammatory diseases (Free Radical Biology and Medicine, 2012).

Other names

Thiol-containing proteinsSulfhydryl-containing proteinsCysteine-rich proteinsIntracellular thiols

Covalent modification of the nucleophilic thiol group of cysteine residues, leading to irreversible or slowly reversible inhibition of protein function (Nature Reviews Drug Discovery, 2016).