Open AccessDesign, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1
Author(s) -
Luca Gambini,
Parima Udompholkul,
Carlo Baggio,
Aruljothi Muralidharan,
Nikola Kenjić,
Z. Assar,
J. Jefferson P. Perry,
Maurizio Pellecchia
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00005
Subject(s) - chemistry , covalent bond , peptide , combinatorial chemistry , rational design , lysine , structure–activity relationship , biochemistry , computational biology , nanotechnology , amino acid , in vitro , organic chemistry , materials science , biology
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.