1. Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1
- Author
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Parima Udompholkul, Carlo Baggio, Zahra Assar, Aruljothi Muralidharan, Luca Gambini, Nikola Kenjić, J. Jefferson P. Perry, and Maurizio Pellecchia
- Subjects
Lysine ,Plasma protein binding ,Computational biology ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Article ,Minor Histocompatibility Antigens ,BH3 peptide ,Proto-Oncogene Proteins ,Drug Discovery ,Humans ,Amino Acid Sequence ,Binding site ,Peptide sequence ,Binding Sites ,Extramural ,Chemistry ,Peptide Fragments ,Up-Regulation ,Kinetics ,Proto-Oncogene Proteins c-bcl-2 ,Design synthesis ,A549 Cells ,Covalent bond ,Drug Design ,Myeloid Cell Leukemia Sequence 1 Protein ,Molecular Medicine ,Protein Binding - Abstract
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. more...
- Published
- 2021
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