title: Electrophilic Helical Peptides That Bond Covalently, Irreversibly, and Selectively in a Protein-Protein Interaction Site.
abstract: Protein-protein interactions mediate most physiological and disease processes. Helix-constrained peptides potently mimic or inhibit these interactions by making multiple contacts over large surface areas. However, despite high affinities, they typically have short lifetimes bound to the protein. Here we insert both a helix-inducing constraint and an adjacent electrophile into the native peptide ligand BIM to target the oncogenic protein Bcl2A1. The modified BIM peptide bonds covalently and irreversibly to one cysteine within the helix-binding groove of Bcl2A1, but not to two other exposed cysteines on its surface, and shows no covalent bonding to other Bcl2 proteins. It also penetrates cell membranes and bonds covalently to Bcl2A1 inside cells. This innovative approach to increasing receptor residence time of helical peptides demonstrates the potential to selectively silence a PPI inside cells, with selectivity over other nucleophilic sites on proteins.
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Aline Dantas
authors.initials: AD
authors.lastname: de Araujo
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.affiliation: Noliva Therapeutics , Newton, Massachusetts 02465, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.affiliation: Noliva Therapeutics , Newton, Massachusetts 02465, United States.
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
keywords: Bcl2; Covalent inhibitor; acrylamide; electrophile; helix; protein−protein interaction