Solvent-exposed cysteine residues on epidermal and cytosolic proteins

Solvent-exposed cysteine residues on epidermal and cytosolic proteins are highly reactive nucleophilic sites that serve as primary targets for both toxic electrophiles and targeted covalent drugs. These residues possess a thiol side chain whose reactivity is often modulated by the local protein environment, allowing for site-specific modifications such as alkylation or redox-based signaling. In toxicology, they are the principal targets of vesicants like sulfur mustard, which cross-links proteins such as p53 and keratins in the skin, leading to severe blistering and cell death. In therapeutic contexts, these residues are exploited by covalent inhibitors to irreversibly bind to specific kinases, providing enhanced efficacy and selectivity. The broad distribution of these reactive sites across the cysteinome makes them central to cellular homeostasis but also poses challenges regarding off-target toxicity and immunogenicity.

Other names

Reactive cysteinesProtein thiolsCysteinomeNucleophilic cysteine residuesTargetable cysteinesSurface-exposed cysteines

Covalent alkylation and Michael addition to nucleophilic thiol groups