Serrano, JC;
Sipthorp, J;
Xu, W;
Itzhaki, LS;
Ley, SV;
(2017)
A New Methodology for Incorporating Chiral Linkers into Stapled Peptides.
ChemBioChem
, 18
(12)
pp. 1066-1071.
10.1002/cbic.201700075.
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Abstract
Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents for modulating protein–protein interactions. Here, we report the first two-component i,i+7 stapling methodology that makes use of two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral centre into a p53-derived stapled peptide. Post-stapling modifications to the chain were performed on-resin and enabled rapid access to various peptide derivatives from a single staple. The stapled peptides have increased helicity, protease stability and in vitro binding affinities to MDM2 compared to the equivalent unstapled peptide. This approach can be used to generate a library of diverse stapled peptides with different properties starting from a single stapled peptide, with scope for much greater functional diversity than that provided by existing stapling methodologies.
| Type: | Article |
|---|---|
| Title: | A New Methodology for Incorporating Chiral Linkers into Stapled Peptides |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cbic.201700075 |
| Publisher version: | http://dx.doi.org/10.1002/cbic.201700075 |
| Language: | English |
| Additional information: | © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Chemistry, Medicinal, Pharmacology & Pharmacy, Chiral Linkers, Protein-Protein Interactions, Solid-Phase Synthesis, Stapled Peptides, Two-Component Stapling, Protein-Protein Interactions, Target Binding-Affinity, Alpha-Helical Peptides, P53 Peptide, Metathesis, Inhibitors, Permeability, Strategies, Networks, Design |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10025199 |
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