α-conotoxin GI triazole-peptidomimetics: potent and stable blockers of a human acetylcholine receptor

Knuhtsen, A., Whitmore, C., McWhinnie, F. S., McDougall, L., Whiting, R., Smith, B. O., Timperley, C. M., Green, A. C., Kinnear, K. I. and Jamieson, A. G. (2018) α-conotoxin GI triazole-peptidomimetics: potent and stable blockers of a human acetylcholine receptor. Chemical Science, (doi:10.1039/C8SC04198A) (Early Online Publication)

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Abstract

The potency and selectivity of conotoxin peptides for neuropathic receptors has made them attractive lead compounds in the development of new therapeutics. Specifically, α-conotoxin GI has been shown to be an unparalleled antagonist of the nicotinic acetylcholine receptor (nAChR). However, as with other peptidic leads, poor protease resistance and the redox instability of the conotoxin scaffold limit bioactivity. To counter this, we have employed the underutilised 1,5-disubstituted 1,2,3-triazole to act as a structural surrogate of the native disulfide bonds. Using an efficient, on-resin ruthenium azide-alkyne cycloaddition (RuAAC), each disulfide bond was replaced in turn and the biological activities quantified. One of the mimetic isomers exhibited a comparable activity to the native toxin, while the other showed no biological effect. The active mimetic isomer 11 was an order of magnitude more stable in plasma than the native GI. The NMR solution structure of the mimetic overlays extremely well with the structure for the native GI demonstrating that the triazole bridge is an exceptional surrogate for the disulfide bridge. Development of this potent and stable mimetic of GI leads us to believe that this strategy will yield many other new conotoxin-inspired probes and therapeutics.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Knuhtsen, Dr Astrid and McWhinnie, Mr Fergus and Jamieson, Dr Andrew and McDougall, Miss Laura
Authors: Knuhtsen, A., Whitmore, C., McWhinnie, F. S., McDougall, L., Whiting, R., Smith, B. O., Timperley, C. M., Green, A. C., Kinnear, K. I., and Jamieson, A. G.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Chemical Science
Publisher:Royal Society of Chemistry
ISSN:2041-6520
ISSN (Online):2041-6539
Published Online:26 November 2018
Copyright Holders:Copyright © 2018 The Royal Society of Chemistry
First Published:First published in Chemical Science 2018
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
738201EPSRC DTP 16/17 and 17/18Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/N509668/1R&I - RESEARCH STRATEGY & INNOVATION