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Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization
Author(s) -
Qian Ziqing,
Rhodes Curran A.,
McCroskey Lucas C.,
Wen Jin,
AppiahKubi George,
Wang David J.,
Guttridge Denis C.,
Pei Dehua
Publication year - 2017
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.201610888
Subject(s) - peptide , bicyclic molecule , chemistry , biophysics , cell , cell membrane , combinatorial chemistry , membrane permeability , proteolytic enzymes , metabolic stability , stereochemistry , membrane , biochemistry , enzyme , biology , in vitro
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.