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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization : The effect of linker length on stability and activity at nicotinic acetylcholine receptors. / Armishaw, Christopher J; Jensen, Anders A; Balle, Lena D; Scott, Krystle C M; Sørensen, Lena; Strømgaard, Kristian.

In: Antioxidants & Redox Signaling, Vol. 14, No. 1, 2011, p. 65-76.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Armishaw, CJ, Jensen, AA, Balle, LD, Scott, KCM, Sørensen, L & Strømgaard, K 2011, 'Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization: The effect of linker length on stability and activity at nicotinic acetylcholine receptors', Antioxidants & Redox Signaling, vol. 14, no. 1, pp. 65-76. https://doi.org/10.1089/ars.2010.3458

APA

Armishaw, C. J., Jensen, A. A., Balle, L. D., Scott, K. C. M., Sørensen, L., & Strømgaard, K. (2011). Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization: The effect of linker length on stability and activity at nicotinic acetylcholine receptors. Antioxidants & Redox Signaling, 14(1), 65-76. https://doi.org/10.1089/ars.2010.3458

Vancouver

Armishaw CJ, Jensen AA, Balle LD, Scott KCM, Sørensen L, Strømgaard K. Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization: The effect of linker length on stability and activity at nicotinic acetylcholine receptors. Antioxidants & Redox Signaling. 2011;14(1):65-76. https://doi.org/10.1089/ars.2010.3458

Author

Armishaw, Christopher J ; Jensen, Anders A ; Balle, Lena D ; Scott, Krystle C M ; Sørensen, Lena ; Strømgaard, Kristian. / Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization : The effect of linker length on stability and activity at nicotinic acetylcholine receptors. In: Antioxidants & Redox Signaling. 2011 ; Vol. 14, No. 1. pp. 65-76.

Bibtex

@article{567a42f0d06d11df825b000ea68e967b,
title = "Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization: The effect of linker length on stability and activity at nicotinic acetylcholine receptors",
abstract = "Modification of alpha-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 alpha-conotoxin AuIB, a selective alpha3beta4 nicotinic acetylcholine receptor antagonist, to examine a range of oligopeptide linker lengths on the oxidative formation of disulfide bonds, activity at nicotinic acetylcholine receptors, and stability to degradation by chymotrypsin. Upon non-directed 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 three-fold decrease in activity for the alpha3beta4 nAChR compared to WT-AuIB, although it was selective for alpha3beta4 over alpha7 and alpha4beta2 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 WT-AuIB. As such, the cAuIB-2 globular isomer could constitute a useful probe for studying the role of the alpha3beta4 nicotinic acetylcholine receptor in a range of in vivo experimental paradigms.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Armishaw, {Christopher J} and Jensen, {Anders A} and Balle, {Lena D} and Scott, {Krystle C M} and Lena S{\o}rensen and Kristian Str{\o}mgaard",
year = "2011",
doi = "10.1089/ars.2010.3458",
language = "English",
volume = "14",
pages = "65--76",
journal = "Antioxidants & Redox Signaling",
issn = "1523-0864",
publisher = "Mary AnnLiebert, Inc. Publishers",
number = "1",

}

RIS

TY - JOUR

T1 - Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization

T2 - The effect of linker length on stability and activity at nicotinic acetylcholine receptors

AU - Armishaw, Christopher J

AU - Jensen, Anders A

AU - Balle, Lena D

AU - Scott, Krystle C M

AU - Sørensen, Lena

AU - Strømgaard, Kristian

PY - 2011

Y1 - 2011

N2 - Modification of alpha-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 alpha-conotoxin AuIB, a selective alpha3beta4 nicotinic acetylcholine receptor antagonist, to examine a range of oligopeptide linker lengths on the oxidative formation of disulfide bonds, activity at nicotinic acetylcholine receptors, and stability to degradation by chymotrypsin. Upon non-directed 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 three-fold decrease in activity for the alpha3beta4 nAChR compared to WT-AuIB, although it was selective for alpha3beta4 over alpha7 and alpha4beta2 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 WT-AuIB. As such, the cAuIB-2 globular isomer could constitute a useful probe for studying the role of the alpha3beta4 nicotinic acetylcholine receptor in a range of in vivo experimental paradigms.

AB - Modification of alpha-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 alpha-conotoxin AuIB, a selective alpha3beta4 nicotinic acetylcholine receptor antagonist, to examine a range of oligopeptide linker lengths on the oxidative formation of disulfide bonds, activity at nicotinic acetylcholine receptors, and stability to degradation by chymotrypsin. Upon non-directed 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 three-fold decrease in activity for the alpha3beta4 nAChR compared to WT-AuIB, although it was selective for alpha3beta4 over alpha7 and alpha4beta2 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 WT-AuIB. As such, the cAuIB-2 globular isomer could constitute a useful probe for studying the role of the alpha3beta4 nicotinic acetylcholine receptor in a range of in vivo experimental paradigms.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1089/ars.2010.3458

DO - 10.1089/ars.2010.3458

M3 - Journal article

C2 - 20649464

VL - 14

SP - 65

EP - 76

JO - Antioxidants & Redox Signaling

JF - Antioxidants & Redox Signaling

SN - 1523-0864

IS - 1

ER -

ID: 22360222