Reactive cysteine residues on cellular proteins

Reactive cysteine residues on cellular proteins, collectively known as the cysteome, represent a diverse class of functional sites characterized by high nucleophilicity and redox sensitivity [1.1.1, 1.4.2]. These residues are unique among amino acids because their reactivity is often modulated by the local protein microenvironment, which can significantly lower the pKa of the thiol group to favor the reactive thiolate anion [1.2.3, 1.4.5]. Biologically, reactive cysteines serve as critical nodes for catalysis, metal coordination, and redox-dependent signaling, and they are frequent sites for post-translational modifications such as S-nitrosylation and oxidation [1.2.1, 1.4.2]. In drug discovery, these residues are targeted by covalent inhibitors that utilize electrophilic warheads to form stable chemical bonds, providing advantages like prolonged target engagement and the ability to hit historically undruggable sites [1.3.1, 1.4.1]. Notable examples include the targeting of Cys797 in EGFR by osimertinib and Cys12 in the KRAS G12C mutant by sotorasib [1.3.1, 1.3.4]. However, the broad distribution of reactive cysteines across the proteome necessitates high selectivity to avoid off-target toxicity and potential immunogenic responses resulting from protein haptenization [1.1.3, 1.3.5].

Other names

CysteomeProtein cysteine thiolsNucleophilic cysteinesHyper-reactive cysteinesDruggable cysteinesFunctional cysteines

Targeted covalent inhibition via Michael addition or nucleophilic substitution, typically involving an electrophilic warhead (e.g., acrylamide) reacting with the cysteine thiolate to form an irreversible or reversible covalent bond.