Structure and activity of (2,8)-dicarba-(3,12)-cystino alpha-ImI, an alpha-conotoxin containing a nonreducible cystine analogue

Journal of Medicinal Chemistry
Christopher A MacRaildR S Norton

Abstract

The alpha-conotoxins are potent and selective antagonists of nicotinic acetylcholine receptors (nAChR). Exploitation of these and other peptides in research and clinical settings has been hampered by the lability of the disulfide bridges that are essential for toxin structure and activity. One solution to this problem is replacement of cystine bridges with nonreducible dicarba linkages. We explore this approach by determining the solution structure and functional characteristics of a dicarba analogue of the alpha-conotoxin alpha-ImI, (2,8)-dicarba-(3,12)-cystino alpha-ImI. The structure of the dicarba analogue was similar to that of native alpha-ImI, with differences attributable to the different covalent geometry of the disulfide and dicarba bridges. Dicarba-alpha-ImI maintained inhibitory activity of nAChR comparable to that of native alpha-ImI in two in vitro assays. These findings confirm the potential of the dicarba linkage to improve stability while maintaining alpha-conotoxin function.

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Citations

May 19, 2009·Acta Pharmacologica Sinica·Layla Azam, J Michael McIntosh
Jul 3, 2013·Marine Drugs·Ryan M BradyRaymond S Norton
Feb 12, 2011·European Biophysics Journal : EBJ·Mohammed Akhter HossainJ Michael Conlon
Nov 19, 2014·Future Medicinal Chemistry·Jutty Rajan PrashanthRichard J Lewis
Nov 19, 2014·Future Medicinal Chemistry·Brad R GreenRaymond S Norton
Feb 28, 2016·FEBS Letters·Beow Keat YapRaymond S Norton
Apr 12, 2017·Expert Opinion on Drug Discovery·Raymond S Norton
Feb 6, 2017·Biochemical and Biophysical Research Communications·Kotaro SakamotoAkiyoshi Tani
Feb 20, 2016·Chemical Communications : Chem Comm·Ellen C GleesonAndrea J Robinson
Jul 28, 2017·Chemistry : a European Journal·Alessandro GoriSilvia Rinaldi
Jun 15, 2018·Marine Drugs·Nikita Abraham, Richard J Lewis
Apr 30, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Raymond S Norton
Jul 14, 2011·Chembiochem : a European Journal of Chemical Biology·Rob M J LiskampJohan Kemmink
Sep 14, 2019·European Biophysics Journal : EBJ·Patrick Brendan TimmonsChandralal M Hewage
Aug 12, 2020·Chemistry, an Asian Journal·Yun-Kun QiLei Liu
Dec 15, 2010·Natural Product Reports·John W BluntMichèle R Prinsep
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Jan 27, 2019·Journal of Peptide Science : an Official Publication of the European Peptide Society·Jan-Patrick FischerAnnette G Beck-Sickinger
Mar 17, 2021·Journal of Medicinal Chemistry·Alessia BelgiAndrea J Robinson
Jun 8, 2021·RSC Medicinal Chemistry·Ashlin TurnerDavid J Craik
Dec 2, 2010·Journal of Medicinal Chemistry·Markus MuttenthalerPaul F Alewood
Apr 12, 2014·Chemical Reviews·Kalyana B AkondiPaul F Alewood
Jan 28, 2020·Journal of Medicinal Chemistry·Pan XuSulan Luo
Nov 14, 2014·Journal of Medicinal Chemistry·Sandeep ChhabraRaymond S Norton

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