A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists

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A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists. / Armishaw, Christopher J; Singh, Narender; Medina-Franco, Jose L; Clark, Richard J; Scott, Krystle C M; Houghten, Richard A; Jensen, Anders Asbjørn.

In: Journal of Biological Chemistry, Vol. 285, No. 3, 2010, p. 1809-1821.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Armishaw, CJ, Singh, N, Medina-Franco, JL, Clark, RJ, Scott, KCM, Houghten, RA & Jensen, AA 2010, 'A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists', Journal of Biological Chemistry, vol. 285, no. 3, pp. 1809-1821. https://doi.org/10.1074/jbc.M109.071183

APA

Armishaw, C. J., Singh, N., Medina-Franco, J. L., Clark, R. J., Scott, K. C. M., Houghten, R. A., & Jensen, A. A. (2010). A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists. Journal of Biological Chemistry, 285(3), 1809-1821. https://doi.org/10.1074/jbc.M109.071183

Vancouver

Armishaw CJ, Singh N, Medina-Franco JL, Clark RJ, Scott KCM, Houghten RA et al. A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists. Journal of Biological Chemistry. 2010;285(3):1809-1821. https://doi.org/10.1074/jbc.M109.071183

Author

Armishaw, Christopher J ; Singh, Narender ; Medina-Franco, Jose L ; Clark, Richard J ; Scott, Krystle C M ; Houghten, Richard A ; Jensen, Anders Asbjørn. / A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 3. pp. 1809-1821.

Bibtex

@article{8d45c40001cc11df825d000ea68e967b,
title = "A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists",
abstract = "alpha-Conotoxins are peptide neurotoxins isolated from venomous cone snails that display exquisite selectivity for different subtypes of nicotinic acetylcholine receptors (nAChR). They are valuable research tools that have profound implications in the discovery of new drugs for a myriad of neuropharmacological conditions. They are characterized by a conserved two-disulfide bond framework, which gives rise to two intervening loops of extensively mutated amino acids that determine their selectivity for different nAChR subtypes. We have used a multistep synthetic combinatorial approach using alpha-conotoxin ImI to develop potent and selective alpha(7) nAChR antagonists. A positional scan synthetic combinatorial library was constructed based on the three residues of the n-loop of alpha-conotoxin ImI to give a total of 10,648 possible combinations that were screened for functional activity in an alpha(7) nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual alpha-conotoxin analogs based on the combinations of defined active amino acid residues from positional scan synthetic combinatorial library screening data were synthesized. Several analogs exhibited significantly improved antagonist activity for the alpha(7) nAChR compared with WT-ImI. Binding interactions between the analogs and the alpha(7) nAChR were explored using a homology model of the amino-terminal domain based on a crystal structure of an acetylcholine-binding protein. Finally, a third series of refined analogs was synthesized based on modeling studies, which led to several analogs with refined pharmacological properties. Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > or =10-fold increases in antagonist potency compared with WT-ImI.",
keywords = "The Faculty of Pharmaceutical Sciences",
author = "Armishaw, {Christopher J} and Narender Singh and Medina-Franco, {Jose L} and Clark, {Richard J} and Scott, {Krystle C M} and Houghten, {Richard A} and Jensen, {Anders Asbj{\o}rn}",
year = "2010",
doi = "10.1074/jbc.M109.071183",
language = "English",
volume = "285",
pages = "1809--1821",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists

AU - Armishaw, Christopher J

AU - Singh, Narender

AU - Medina-Franco, Jose L

AU - Clark, Richard J

AU - Scott, Krystle C M

AU - Houghten, Richard A

AU - Jensen, Anders Asbjørn

PY - 2010

Y1 - 2010

N2 - alpha-Conotoxins are peptide neurotoxins isolated from venomous cone snails that display exquisite selectivity for different subtypes of nicotinic acetylcholine receptors (nAChR). They are valuable research tools that have profound implications in the discovery of new drugs for a myriad of neuropharmacological conditions. They are characterized by a conserved two-disulfide bond framework, which gives rise to two intervening loops of extensively mutated amino acids that determine their selectivity for different nAChR subtypes. We have used a multistep synthetic combinatorial approach using alpha-conotoxin ImI to develop potent and selective alpha(7) nAChR antagonists. A positional scan synthetic combinatorial library was constructed based on the three residues of the n-loop of alpha-conotoxin ImI to give a total of 10,648 possible combinations that were screened for functional activity in an alpha(7) nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual alpha-conotoxin analogs based on the combinations of defined active amino acid residues from positional scan synthetic combinatorial library screening data were synthesized. Several analogs exhibited significantly improved antagonist activity for the alpha(7) nAChR compared with WT-ImI. Binding interactions between the analogs and the alpha(7) nAChR were explored using a homology model of the amino-terminal domain based on a crystal structure of an acetylcholine-binding protein. Finally, a third series of refined analogs was synthesized based on modeling studies, which led to several analogs with refined pharmacological properties. Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > or =10-fold increases in antagonist potency compared with WT-ImI.

AB - alpha-Conotoxins are peptide neurotoxins isolated from venomous cone snails that display exquisite selectivity for different subtypes of nicotinic acetylcholine receptors (nAChR). They are valuable research tools that have profound implications in the discovery of new drugs for a myriad of neuropharmacological conditions. They are characterized by a conserved two-disulfide bond framework, which gives rise to two intervening loops of extensively mutated amino acids that determine their selectivity for different nAChR subtypes. We have used a multistep synthetic combinatorial approach using alpha-conotoxin ImI to develop potent and selective alpha(7) nAChR antagonists. A positional scan synthetic combinatorial library was constructed based on the three residues of the n-loop of alpha-conotoxin ImI to give a total of 10,648 possible combinations that were screened for functional activity in an alpha(7) nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual alpha-conotoxin analogs based on the combinations of defined active amino acid residues from positional scan synthetic combinatorial library screening data were synthesized. Several analogs exhibited significantly improved antagonist activity for the alpha(7) nAChR compared with WT-ImI. Binding interactions between the analogs and the alpha(7) nAChR were explored using a homology model of the amino-terminal domain based on a crystal structure of an acetylcholine-binding protein. Finally, a third series of refined analogs was synthesized based on modeling studies, which led to several analogs with refined pharmacological properties. Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > or =10-fold increases in antagonist potency compared with WT-ImI.

KW - The Faculty of Pharmaceutical Sciences

U2 - 10.1074/jbc.M109.071183

DO - 10.1074/jbc.M109.071183

M3 - Journal article

VL - 285

SP - 1809

EP - 1821

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 3

ER -

ID: 17005722