Cellular and plasma proteins with nucleophilic residues

Cellular and plasma proteins with nucleophilic residues represent a broad and heterogeneous group of proteins, including Human Serum Albumin and various intracellular enzymes, that possess reactive functional groups like thiols or amines. These proteins are generally not intended therapeutic targets; instead, they often serve as sites for non-specific covalent binding by electrophilic drugs or reactive metabolites (Park et al., 2011, Nature Reviews Drug Discovery). While these proteins can act as protective 'sinks' by scavenging reactive species, the resulting covalent protein-drug adducts can impair biological functions or act as haptens that trigger immune-mediated adverse drug reactions (Uetrecht, 2008, Chemical Research in Toxicology). This phenomenon is a primary mechanism underlying idiosyncratic drug-induced liver injury (DILI) and other severe toxicities (Liebler, 2008, Chemical Research in Toxicology). In drug development, the extent of covalent binding to these nucleophilic residues is closely monitored to assess safety risks and to guide the design of more selective covalent inhibitors that minimize off-target interactions (Bauer, 2015, Analysis of Covalent Inhibitors). Consequently, understanding the reactivity of these proteins is critical for predicting and mitigating drug-related safety concerns.

Other names

Nucleophilic protein targetsElectrophile-reactive proteinsCovalent adduct-forming proteinsOff-target nucleophilic proteins

Covalent modification of nucleophilic amino acid side chains (such as the thiol group of cysteine, the epsilon-amino group of lysine, or the imidazole group of histidine) by electrophilic drug molecules or their reactive metabolic intermediates (Kalgutkar et al., 2005).