Cellular proteins with nucleophilic amino acids

Cellular proteins with nucleophilic amino acids represent a broad and diverse class of biological molecules characterized by the presence of reactive side chains, most notably the thiol group of cysteine, the primary amine of lysine, and the hydroxyl groups of serine, threonine, and tyrosine (Source: Nature Reviews Drug Discovery, 2011, 10, 307-317). These residues act as nucleophiles that can form stable, often irreversible, covalent bonds with electrophilic functional groups on small molecule drugs, a strategy known as covalent inhibition. This mechanism allows for high potency and a prolonged duration of action that is independent of the drug's systemic half-life, as the effect lasts until the protein is resynthesized (Source: Journal of Medicinal Chemistry, 2015, 58, 13, 5171–5184). While this approach has been successfully applied to targets like EGFR and BTK in oncology, the term itself describes a chemical property of a vast subset of the proteome rather than a single therapeutic entity. Consequently, the primary challenge in drug development is achieving sufficient selectivity for a specific protein's nucleophilic residue to avoid off-target reactivity with the broader 'nucleophilic proteome,' which can lead to toxicity or immunogenic responses (Source: ACS Chemical Biology, 2017, 12, 3, 599–612).

Other names

Nucleophilic proteomeCovalent drug targetsReactive amino acid residuesElectrophile-responsive proteins

Covalent modification of nucleophilic residues (e.g., Cys, Lys, Ser) via electrophilic attack, leading to irreversible or reversible-covalent inhibition of protein function.