2016
DOI: 10.1002/anie.201610888
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Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization

Abstract: Therapeutic applications of peptides are currently limited by their proteolytic instability and impermeability to the cell membrane. Here, we report a general, reversible bicyclization strategy 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 prot… Show more

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Cited by 65 publications
(65 citation statements)
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References 40 publications
(48 reference statements)
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“…This inhibitor may serve as a useful tool for investigating the biological function of TCPTP in signalling pathways. Together with our previously reported examples, 6,7 this work demonstrates that bicyclic peptides featuring both cell-penetrating and target-binding units may provide a general strategy for developing cell-permeable ligands against intracellular proteins.…”
supporting
confidence: 74%
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“…This inhibitor may serve as a useful tool for investigating the biological function of TCPTP in signalling pathways. Together with our previously reported examples, 6,7 this work demonstrates that bicyclic peptides featuring both cell-penetrating and target-binding units may provide a general strategy for developing cell-permeable ligands against intracellular proteins.…”
supporting
confidence: 74%
“…The bicyclic approach was subsequently shown to be effective for delivering a wide variety of peptide sequences including negatively charged phosphopeptides into the cytosol of mammalian cells. 7 In this study, we set out to test whether the bicyclic peptide approach might be applied to generate isoform-specific inhibitors against other members of the PTP superfamily.…”
mentioning
confidence: 99%
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“…To render the linear peptide ligands cell-permeable and proteolytically stable, Qian et al devised reversible cyclization strategies, in which the linear peptide ligands were fused with a short CPP motif (e.g., Arg-Arg-Arg-Arg-Nal-Phe) and cyclized into mono- or bicyclic structures by disulphide bond(s) [51,52]. When outside the cell (e.g., in serum), the cyclic peptides have dramatically improved cellular uptake efficiency and metabolic stability relative to their linear precursors.…”
Section: Cell-permeable Cyclic Peptide Ppi Inhibitorsmentioning
confidence: 99%
“…However, its low potency and poor pharmacokinetics (e.g., serum half-life of ~15 min) prevented further clinical development. We 38 and others 39 have attempted to improve the potency, proteolytic stability, and/or cell-permeability of Antp-NBD through cyclization, but the potency of the resulting peptides remained rather modest (IC 50 in the low μ M range). In this work, we have discovered a relatively potent bicyclic peptidyl inhibitor against the NEMO-IKK interaction (IC 50 =1.0 μ M), by screening of a combinatorial library followed by limited optimization.…”
Section: Introductionmentioning
confidence: 99%