Morgan, D. C., McDougall, L., Knuhtsen, A. and Jamieson, A. (2023) Development of bifunctional, Raman active diyne‐girder stapled α‐helical peptides. Chemistry: A European Journal, (doi: 10.1002/chem.202300855) (PMID:37130830) (Early Online Publication)
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Abstract
Stapled peptides are a unique class of cyclic α-helical peptides that are conformationally constrained via their amino acid side-chains. They have been transformative to the field of chemical biology and peptide drug discovery through addressing many of the physicochemical limitations of linear peptides. However, there are several issues with current chemical strategies to produce stapled peptides. For example, two distinct unnatural amino acids are required to synthesise i, i + 7 alkene stapled peptides, leading to high production costs. Furthermore, low purified yields are obtained due to cis/trans isomers produced during ring-closing metathesis macrocyclisation. Here we report the development of a new i, i + 7 diyne-girder stapling strategy that addresses these issues. The asymmetric synthesis of nine unnatural Fmoc-protected alkyne-amino acids facilitated a systematic study to determine the optimal (S,S)-stereochemistry and 14-carbon diyne-girder bridge length. Diyne-girder stapled T-STAR peptide 29 was demonstrated to have excellent helicity, cell permeability and stability to protease degradation. Finally, we demonstrate that the diyne-girder constraint is a Raman chromophore with potential use in Raman cell microscopy. Development of this highly effective, bifunctional diyne-girder stapling strategy leads us to believe that it can be used to produce other stapled peptide probes and therapeutics.
| Item Type: | Articles |
|---|---|
| Additional Information: | The authors thank the University of Glasgow, EPSRC (Research Project Grant EP/L018152/1) and the Defence Science and Technology Laboratory (Research Project Grant DSTL/AGR/ R/CBRN/01 and DSTLX1000141308) for financial support of this research. D.C.M. and L.M. thank the EPSRC for studentships (EP/N509668/1 and EP/R513222/1). |
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morgan, Dr Danielle and Jamieson, Professor Andrew and Knuhtsen, Dr Astrid and McDougall, Miss Laura |
| Authors: | Morgan, D. C., McDougall, L., Knuhtsen, A., and Jamieson, A. |
| College/School: | College of Science and Engineering > School of Chemistry |
| Journal Name: | Chemistry: A European Journal |
| Publisher: | Wiley |
| ISSN: | 0947-6539 |
| ISSN (Online): | 1521-3765 |
| Published Online: | 02 May 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Chemistry: A European Journal 2023 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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