Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl‑1

Modulating
disease-relevant protein–protein interactions
(PPIs) using pharmacological tools is a critical step toward the design
of novel therapeutic strategies. Over the years, however, targeting
PPIs has proven a very challenging task owing to the large interfacial
areas. Our recent efforts identified possible novel routes for the
design of potent and selective inhibitors of PPIs using a structure-based
design of covalent inhibitors targeting Lys residues. In this present
study, we report on the design, synthesis, and characterizations of
the first Lys-covalent BH3 peptide that has a remarkable affinity
and selectivity for hMcl-1 over the closely related hBfl-1 protein.
Our structural studies, aided by X-ray crystallography, provide atomic-level
details of the inhibitor interactions that can be used to further
translate these discoveries into novel generation, Lys-covalent pro-apoptotic
agents.