Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization. Issue 6 (30th December 2016)

• Record Type: Journal Article
• Authors: Qian, Ziqing; Rhodes, Curran A.; McCroskey, Lucas C.; Wen, Jin; Appiah‐Kubi, George; Wang, David J.; Guttridge, Denis C.; Pei, Dehua
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 6(2017)
• Page Start: 1525
• Page End: 1529
• Publication Date: 2016-12-30
• Subjects: bicyclization -- cell-penetrating peptides -- cyclic peptides -- nemo inhibitors -- protein–protein interactions; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201610888
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : In the loop : Peptide bicyclization by a pair of disulfide bonds increases its proteolytic stability and cell permeability. This method also allows for regeneration of the functional linear peptide once inside the cytosol of the cell. CPP=cell‐penetrating peptide.