Protein disulfide bonds and reactive cysteine residues

Protein disulfide bonds and reactive cysteine residues represent critical structural and functional elements across a wide array of the human proteome. Reactive cysteines, characterized by their low pKa and high nucleophilicity, often serve as catalytic centers in enzymes or as sensors for redox signaling (Backus et al., Nature Chemical Biology, 2016). Disulfide bonds, formed by the oxidation of two cysteine thiols, are essential for maintaining the structural integrity of secreted and membrane-bound proteins (Hogg, Trends in Biochemical Sciences, 2003). In modern pharmacology, these sites are frequently targeted by covalent inhibitors, such as Ibrutinib and Afatinib, which form irreversible bonds with specific cysteine residues to achieve high potency and prolonged duration of action (Bauer, Drug Discovery Today, 2015). These residues are also involved in the mechanism of action for redox-modulating drugs like N-acetylcysteine and dimethyl fumarate, which alter the cellular thiol-disulfide balance (Khoo et al., Antioxidants & Redox Signaling, 2018). While targeting these residues allows for high selectivity in certain kinases, it also poses risks of off-target reactivity and potential immunogenicity due to the formation of protein-drug adducts (Lonsdale et al., Chemical Society Reviews, 2017). Consequently, these moieties are viewed as both high-value therapeutic "handles" and significant challenges in drug safety assessment.

Other names

Cysteine thiolsDisulfide bridgesReactive protein thiolsCovalent targeting sitesProtein sulfhydryl groups

Covalent modification of cysteine thiols via Michael addition or nucleophilic substitution, and modulation of redox states through disulfide bond reduction or thiol-disulfide exchange.