Redox-sensitive cysteine residues

Redox-sensitive cysteine residues are highly reactive thiol-containing amino acids that serve as critical sensors and regulators of cellular signaling and oxidative stress. These residues possess a lower pKa than typical cysteines, allowing them to exist as nucleophilic thiolate anions at physiological pH, which makes them susceptible to modifications such as sulfenylation, nitrosylation, and covalent bonding with electrophilic molecules (PMID: 21810451). In drug discovery, these residues are targeted by electrophilic small molecules, known as covalent inhibitors, to achieve potent and prolonged modulation of therapeutic targets like Bruton's tyrosine kinase (BTK) and the epidermal growth factor receptor (EGFR) (PMID: 26030318). For instance, dimethyl fumarate targets specific cysteines on the KEAP1 protein to activate the Nrf2 antioxidant response, providing neuroprotective and anti-inflammatory effects in multiple sclerosis (PMID: 23515050). While targeting these residues offers advantages in potency and selectivity, it also carries risks of off-target reactivity and the formation of haptens, which can trigger immune-mediated adverse reactions. Consequently, the development of drugs targeting these residues requires careful optimization of electrophilicity to balance reactivity with target specificity.

Other names

Reactive cysteinesNucleophilic cysteinesThiol switchesElectrophile-responsive elementsCysteine-based redox sensors

Covalent modification of nucleophilic cysteine thiol groups via Michael addition or nucleophilic substitution, leading to irreversible or slowly reversible protein inhibition or activation.