Covalent Ligand Electrophiles Are Differentially Activated by Proximity Effects Which Govern Latent Protein Reactivity.

ABSTRACT: Covalent ligands contain an electrophilic moiety that reacts with a nucleophilic residue on a target protein, following an initial reversible binding event. Covalent ligand development typically involves efforts to increase on-target selectivity by maximizing the ligand binding affinity and minimizing intrinsic electrophile reactivity. Problematically, this limits labeling kinetics and requires high affinity ligands. The concept of "latency" describes the potential for "turn-on" activation of electrophiles upon target engagement. Here, we investigate the potential intrinsic latency of covalent electrophiles and test the hypothesis that diverse electrophiles can be differentially activated by proximity effects. We develop a kinetic effective molarity (EM _k ) approach to qu

SUBMITTER: Frankovich TV 

PROVIDER: S-EPMC12550623 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature