Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization.

Qian Z, Rhodes CA, McCroskey LC, Wen J, Appiah-Kubi G, Wang DJ, Guttridge DC, Pei D
Angew Chem Int Ed Engl 56 1525-1529 01/01/2017


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.

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