A synthetic combinatorial strategy for developing alpha-conotoxin analogs as potent alpha7 nicotinic acetylcholine receptor antagonists

Armishaw, Christopher J., Singh, Narender, Medina-Franco, Jose L., Clark, Richard J., Scott, Krystle C. M., Houghten, Richard A. and Jensen, Anders A. (2009) A synthetic combinatorial strategy for developing alpha-conotoxin analogs as potent alpha7 nicotinic acetylcholine receptor antagonists. Journal of Biological Chemistry, 285 3: 1809-1821. doi:10.1074/jbc.M109.071183

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Author Armishaw, Christopher J.
Singh, Narender
Medina-Franco, Jose L.
Clark, Richard J.
Scott, Krystle C. M.
Houghten, Richard A.
Jensen, Anders A.
Title A synthetic combinatorial strategy for developing alpha-conotoxin analogs as potent alpha7 nicotinic acetylcholine receptor antagonists
Formatted title
A synthetic combinatorial strategy for developing α-conotoxin analogs as potent α7 nicotinic acetylcholine receptor antagonists
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2009-11-09
Year available 2009
Sub-type Article (original research)
DOI 10.1074/jbc.M109.071183
Open Access Status File (Publisher version)
Volume 285
Issue 3
Start page 1809
End page 1821
Total pages 13
Editor Herbert Tabor
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry & Molecular Biology
Collection year 2010
Language eng
Subject C1
970103 Expanding Knowledge in the Chemical Sciences
030406 Proteins and Peptides
030401 Biologically Active Molecules
Formatted abstract
α-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 α-conotoxin ImI to develop potent and selective α7 nAChR antagonists. A positional scan synthetic combinatorial library was constructed based on the three residues of the n-loop of α-conotoxin ImI to give a total of 10,648 possible combinations that were screened for functional activity in an α7 nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual α-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 α7 nAChR compared with WT-ImI. Binding interactions between the analogs and the α7 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 α-conotoxin analogs synthesized, three displayed ≥10-fold increases in antagonist potency compared with WT-ImI.
Keyword Peptide Libraries
Molecular dynamics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 26 times in Scopus Article | Citations
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Created: Sun, 24 Jan 2010, 00:03:27 EST