title: Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity.
abstract: A general strategy was developed for the intracellular delivery of linear peptidyl ligands through fusion to a cell-penetrating peptide and cyclization of the fusion peptides via a disulfide bond. The resulting cyclic peptides are cell permeable and have improved proteolytic stability. Once inside the cell, the disulfide bond is reduced to produce linear biologically active peptides. This strategy was applied to generate a cell-permeable peptide substrate for real-time detection of intracellular caspase activities during apoptosis and an inhibitor for the CFTR-associated ligand (CAL) PDZ domain as a potential treatment for cystic fibrosis.
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.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Jeanine F
authors.initials: JF
authors.lastname: Amacher
authors.forename: Dean R
authors.initials: DR
authors.lastname: Madden
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D003500:Cyclization; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000378:metabolism*; D016503:Drug Delivery Systems; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D054731:PDZ Domains / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: PDZ domains; cell‐penetrating peptides; cyclic peptides; cystic fibrosis; protein–protein interactions