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Issue 6, 2019
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α-Conotoxin GI triazole-peptidomimetics: potent and stable blockers of a human acetylcholine receptor

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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.

Graphical abstract: α-Conotoxin GI triazole-peptidomimetics: potent and stable blockers of a human acetylcholine receptor

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Publication details

The article was received on 20 Sep 2018, accepted on 24 Nov 2018 and first published on 26 Nov 2018


Article type: Edge Article
DOI: 10.1039/C8SC04198A
Chem. Sci., 2019,10, 1671-1676
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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

    A. Knuhtsen, C. Whitmore, F. S. McWhinnie, L. McDougall, R. Whiting, B. O. Smith, C. M. Timperley, A. C. Green, K. I. Kinnear and A. G. Jamieson, Chem. Sci., 2019, 10, 1671
    DOI: 10.1039/C8SC04198A

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