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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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A549 Cells
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Amino Acid Sequence
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Binding Sites
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Crystallography, X-Ray
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Drug Design*
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Humans
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Kinetics
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Lysine / chemistry*
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Minor Histocompatibility Antigens / chemistry
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Minor Histocompatibility Antigens / metabolism
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Molecular Dynamics Simulation
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Peptide Fragments / chemical synthesis
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Peptide Fragments / chemistry*
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Peptide Fragments / pharmacology
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Protein Binding
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Proto-Oncogene Proteins / chemical synthesis
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Up-Regulation / drug effects
Substances
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BCL2-related protein A1
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Bax protein (53-86)
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Lysine