Proteins with reactive active-site cysteine

Proteins with reactive active-site cysteines represent a broad and functionally diverse class of enzymes and signaling molecules that utilize a highly nucleophilic cysteine residue for their catalytic or regulatory mechanisms (Weerapana et al., 2010). This group includes major enzyme families such as cysteine proteases (e.g., caspases and cathepsins), protein tyrosine phosphatases (PTPs), and deubiquitinating enzymes (DUBs), as well as specific kinases where a cysteine residue in the ATP-binding pocket is accessible for targeting (Turk et al., 2012; Singh et al., 2011). The unique chemical reactivity of the cysteine thiol in these specific protein environments makes them ideal candidates for covalent drug design, allowing for high potency and a prolonged duration of action that is independent of the drug's systemic half-life (Singh et al., 2011). Covalent inhibitors, such as the kinase inhibitor ibrutinib and the antiviral nirmatrelvir, feature electrophilic 'warheads' that form permanent bonds with these reactive cysteines to achieve therapeutic effects (Honigberg et al., 2010; Owen et al., 2021). However, the inherent reactivity of these sites also presents significant safety challenges, including the risk of off-target modifications and the potential for hapten formation, which can trigger idiosyncratic immune responses (Baillie, 2016). Consequently, achieving high selectivity is a primary focus in the development of therapeutics targeting this protein class.

Other names

Cysteine-dependent enzymesCysteine-based catalystsNucleophilic cysteine-containing proteinsCysteine proteome targets

Covalent inhibition via nucleophilic attack by a reactive active-site cysteine thiol on an electrophilic moiety (warhead) of the drug, forming a stable covalent adduct that irreversibly or semi-irreversibly blocks protein function (Singh et al., 2011).