title: Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics.
abstract: We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subunits low enough that an α-helix-like conformation can be adopted but high enough to interfere with protease activity. Previous studies with a different protein-recognition system that suggested ring-constrained β residues can be superior to flexible β residues in terms of maximizing α/β-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained β residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic β residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-xL and Mcl-1. Overall, this study helps to establish that α/β-peptides containing ring-preorganized β residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize α-helical partners.
authors.affiliation: †Department of Chemistry, University of Wisconsin, 1101 University Ave., Madison, Wisconsin 53706, United States.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Peterson-Kaufman
authors.affiliation: †Department of Chemistry, University of Wisconsin, 1101 University Ave., Madison, Wisconsin 53706, United States.
authors.forename: Holly S
authors.initials: HS
authors.lastname: Haase
authors.affiliation: †Department of Chemistry, University of Wisconsin, 1101 University Ave., Madison, Wisconsin 53706, United States.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Boersma
authors.affiliation: §Structural Biology Division, The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|‡Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.affiliation: §Structural Biology Division, The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|‡Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.affiliation: †Department of Chemistry, University of Wisconsin, 1101 University Ave., Madison, Wisconsin 53706, United States.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: C474007:Bax protein (53-86); D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein