Other cell-surface proteins with accessible lysine residues

The term "Other cell-surface proteins with accessible lysine residues" refers to a broad category of membrane-associated proteins that possess lysine side chains (epsilon-amino groups) exposed to the extracellular environment (Hermanson, G. T., Bioconjugate Techniques, 2013 [1]). These primary amines are highly nucleophilic and serve as the primary chemical handles for the covalent attachment of drugs, linkers, and imaging probes through electrophilic substitution or addition reactions (Agarwal & Bertozzi, Bioconjugate Chemistry, 2015 [2]). In a therapeutic context, this is not a single biological target but rather a chemical site of action for non-specific cross-linking agents or the methodology used to generate first-generation antibody-drug conjugates (ADCs) (ChEMBL Database [3]). Because lysine is one of the most abundant amino acids on protein surfaces, targeting these residues typically results in a heterogeneous mixture of modified proteins, which can complicate the pharmacokinetic and safety profiles of the resulting therapeutic (Nature Reviews Drug Discovery, 2022 [4]). Consequently, while essential for many bioconjugation strategies, this 'target' lacks the specificity required for traditional receptor-mediated drug design.

Other names

Surface-exposed lysine residuesCell-surface primary aminesLysine-rich surface proteinsReactive surface amines

Covalent modification of the epsilon-amino group of lysine residues through nucleophilic attack on electrophilic reagents, such as aldehydes or NHS esters, to form stable conjugates.