title: Screening bicyclic peptide libraries for protein-protein interaction inhibitors: discovery of a tumor necrosis factor-α antagonist.
abstract: Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well-defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-α (TNFα) identified a potent antagonist that inhibits the TNFα-TNFα receptor interaction and protects cells from TNFα-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Lian
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA.
authors.forename: Punit
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA.
authors.forename: Curran A
authors.initials: CA
authors.lastname: Rhodes
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA.
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D055808:Drug Discovery; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D019151:Peptide Library; D010455:Peptides; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha