title: Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization.
abstract: Therapeutic applications of peptides are currently limited by their proteolytic instability and impermeability to the cell membrane. A general, reversible bicyclization strategy is now reported to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Curran A
authors.initials: CA
authors.lastname: Rhodes
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: McCroskey
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: George
authors.initials: G
authors.lastname: Appiah-Kubi
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Wang
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Dehua
authors.identifier: 0000-0002-2057-6934
authors.initials: D
authors.lastname: Pei
mesh_terms: D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D004355:Drug Stability; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010599:Pharmacokinetics; D060066:Protein Interaction Maps / Q000187:drug effects*; D059748:Proteolysis; D060327:Solid-Phase Synthesis Techniques
chemical_list: D057846:Cell-Penetrating Peptides; C491731:IKBKG protein, human; D010456:Peptides, Cyclic; D051550:I-kappa B Kinase
keywords: bicyclization; cell-penetrating peptides; cyclic peptides; nemo inhibitors; protein-protein interactions