Protein and small-molecule disulfide bonds

Protein and small-molecule disulfide bonds, often referred to as mixed disulfides or S-thiolation, are covalent chemical linkages formed between a sulfur atom of a protein cysteine residue and a sulfur atom of a small molecule (Ghezzi, 2005, PubMed). These bonds are critical components of cellular redox homeostasis and serve as a reversible post-translational modification that protects proteins from permanent oxidative damage while regulating their biological activity (Ghezzi, 2005, PubMed). Although not a single biological target, the formation of these bonds is the primary mechanism of action for several important drugs; for example, proton pump inhibitors like omeprazole form disulfide bonds with the H+/K+ ATPase to inhibit gastric acid secretion (Shin et al., 2008, PubMed), and disulfiram inactivates aldehyde dehydrogenase through a similar exchange process (Koppaka et al., 2012, PubMed). In drug discovery, the targeted formation of these bonds is a niche strategy for covalent inhibition, requiring high selectivity to avoid interference from the high concentrations of endogenous thiols such as glutathione (PubChem). Monitoring the prevalence of these bonds, particularly S-glutathionylation, provides valuable insights into the oxidative stress levels and metabolic health of a biological system (NIH).

Other names

Mixed disulfidesProtein-small molecule disulfidesS-thiolationS-glutathionylationThiol-disulfide exchange adducts

Covalent modification of protein cysteine residues via thiol-disulfide exchange or reaction with reactive drug intermediates (such as sulfenamides) to form a stable or reversible disulfide bridge (Shin et al., 2008, PubMed; Koppaka et al., 2012, PubMed).