Cellular proteins containing reactive cysteine residues

Cellular proteins containing reactive cysteine residues represent a broad and heterogeneous class of proteins characterized by the presence of nucleophilic thiol groups that are highly susceptible to covalent modification by electrophilic compounds (DrugBank, DB08908). This collective target is primarily associated with the mechanism of action of electrophilic drugs such as dimethyl fumarate and bardoxolone methyl, which utilize Michael addition to form stable adducts with cysteine side chains (Nature Reviews Drug Discovery, 2016). One of the most well-characterized interactions within this group is the modification of KEAP1, which leads to the stabilization of Nrf2 and the subsequent induction of antioxidant and anti-inflammatory gene expression (PubMed, PMID: 26035151). Because these reactive cysteines are found across a wide variety of functional protein classes, including enzymes, transcription factors, and structural proteins, targeting them results in broad systemic effects rather than a single molecular outcome. While this multi-target approach can be therapeutically beneficial for complex diseases like multiple sclerosis and chronic kidney disease, it also poses significant challenges regarding specificity and the potential for off-target toxicity due to the widespread nature of the cysteine proteome.

Other names

Cysteine proteomeReactive thiolsNucleophilic cysteine residuesCysteine-containing proteins

Covalent modification of nucleophilic sulfhydryl groups on cysteine residues via Michael addition or other electrophilic reactions.