Proteins with nucleophilic residues

Proteins with nucleophilic residues refers to a broad and diverse class of proteins characterized by the presence of reactive amino acid side chains, such as the thiol group of cysteine, the hydroxyl group of serine or threonine, or the amine group of lysine (Singh et al., 2011, Nature Reviews Drug Discovery). These residues are often essential for the protein's biological function, serving as catalytic nucleophiles in enzymes or as sites for regulatory post-translational modifications (Backus et al., 2016, Nature). In pharmacology, these nucleophilic sites are strategically targeted by electrophilic small molecules to form stable covalent bonds, leading to potent and long-lasting inhibition of the protein's activity (Bauer, 2015, Journal of Medicinal Chemistry). While this mechanism is utilized by many successful drugs, such as ibrutinib (targeting BTK) and aspirin (targeting COX-1), the term itself describes a chemical property shared by thousands of distinct proteins rather than a specific therapeutic entity. Consequently, it is considered a functional category rather than a discrete target. The primary challenge in drug development for this class is achieving high selectivity to avoid off-target reactivity, which can lead to toxicity or the formation of immunogenic protein-drug adducts (Lonsdale et al., 2017, Chemical Society Reviews).

Other names

Nucleophilic proteinsCovalent drug targetsProteins with reactive residuesElectrophile-sensitive proteins

Covalent modification of nucleophilic amino acid side chains (e.g., Cys, Ser, Lys, His) by electrophilic drug moieties, resulting in irreversible or slowly reversible inhibition of protein function.