Improving the stability of α-conotoxin AuIB through N-to-C cyclization: the effect of linker length on stability and activity at nicotinic acetylcholine receptors

Antioxidants & Redox Signaling
Christopher ArmishawKristian Strømgaard

Abstract

Modification of α-conotoxin frameworks through cyclization via an oligopeptide linker has previously been shown as an effective strategy for improving in vivo stability. We have extended this strategy by investigating cyclic analogs of α-conotoxin AuIB, a selective α(3)β(4) nicotinic acetylcholine receptor (nAChR) antagonist, to examine a range of oligopeptide linker lengths on the oxidative formation of disulfide bonds, activity at nAChRs, and stability to degradation by chymotrypsin. Upon nondirected random oxidation, the ribbon isomer formed preferentially with the globular isomer occurring as a minor by-product. Therefore, a regioselective disulfide bond forming strategy was used to prepare the cAuIB-2 globular isomer in high yield and purity. The cAuIB-2 globular isomer exhibited a threefold decrease in activity for the α(3)β(4) nAChR compared to wild-type-AuIB, although it was selective for α(3)β(4) over α(7) and α(4)β(2) subtypes. On the other hand, the cAuIB-2 ribbon isomer was shown to be inactive at all three nAChR subtypes. Nonetheless, all of the cyclic analogs were found to be significantly more stable to degradation by chymotrypsin than wild-type AuIB. As such, the cAuIB-2 globular isomer could constitute a useful...Continue Reading

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Citations

Sep 21, 2010·Antioxidants & Redox Signaling·David J Craik
Jul 18, 2012·Future Medicinal Chemistry·Christina I Schroeder, David J Craik
Nov 19, 2014·Future Medicinal Chemistry·Jutty Rajan PrashanthRichard J Lewis
Oct 23, 2014·Protein Engineering, Design & Selection : PEDS·Katsiaryna Tarasava, Eva Freisinger
Apr 12, 2014·Chemical Reviews·Kalyana B AkondiPaul F Alewood
Nov 30, 2012·Journal of Peptide Science : an Official Publication of the European Peptide Society·Reena GyandaChristopher J Armishaw
Jul 12, 2014·Regulatory Toxicology and Pharmacology : RTP·Parashar ThapaJon-Paul Bingham
May 20, 2016·ACS Applied Materials & Interfaces·Man YingWeiyue Lu
Oct 11, 2016·Expert Opinion on Drug Discovery·Andrew M White, David J Craik
Aug 31, 2017·The Journal of Biological Chemistry·Xiaosa WuDavid J Craik

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR

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