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Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity
Author(s) -
Qian Ziqing,
Xu Xiaohua,
Amacher Jeanine F.,
Madden Dean R.,
CormetBoyaka Estelle,
Pei Dehua
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201411594
Subject(s) - intracellular , pdz domain , chemistry , peptide , cystic fibrosis transmembrane conductance regulator , cyclic peptide , biophysics , ligand (biochemistry) , fusion protein , cell penetrating peptide , peptide bond , apoptosis , biochemistry , microbiology and biotechnology , recombinant dna , receptor , biology , gene
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.