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Synthesis, Structure Elucidation, in Vitro Biological Activity, Toxicity, and Caco-2 Cell Permeability of Lipophilic Analogues of α-Conotoxin MII

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School of Pharmacy, Institute for Molecular Bioscience, and School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia
Cite this: J. Med. Chem. 2003, 46, 7, 1266–1272
Publication Date (Web):March 4, 2003
https://doi.org/10.1021/jm020426j
Copyright © 2003 American Chemical Society

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    Abstract

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    The α-conotoxin MII is a two disulfide bridge containing, 16 amino acid long peptide toxin isolated from the marine snail Conus magus. This toxin has been found to be a highly selective and potent inhibitor of neuronal nicotinic acetylcholine receptors (nAChRs) of the subtype α3β2. To improve the bioavailability of this peptide, two lipidic analogues of MII have been synthesized, the first by coupling 2-amino-d,l-dodecanoic acid (Laa) to the N terminus (LaaMII) and the second by replacing Asn5 in the MII sequence with this lipoamino acid (5LaaMII). Both lipidic linear peptides were then oxidized under standard conditions. 1H NMR shift analysis of these peptides and comparison with the native MII peptide showed that the tertiary structure of the N-conjugated analogue, LaaMII, was consistent with that of the native conotoxin, whereas the 5LaaMII analogue formed the correct disulfide bridges but failed to adopt the native helical tertiary structure. The N terminus conjugate was also found to inhibit nAChRs of the subtype α3β2 with equal potency to the parent peptide, whereas the 5LaaMII analogue showed no inhibitory activity. The active LaaMII analogue was found to exhibit significantly improved permeability across Caco-2 cell monolayers compared to the native MII, and both peptides showed negligible toxicity.

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     School of Pharmacy.

     Institute for Molecular Bioscience.

    §

     School of Biomedical Sciences.

    *

     Address correspondence to this author at the School of Pharmacy, The University of Queensland, St. Lucia, QLD, Australia 4072 (telephone +61 7 3365 1386; fax +61 7 3365 1688; e-mail I.Toth@ pharmacy.uq.edu.au).

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    Tables of the 1H shifts of MII, LaaMII, and 5LaaMII in 40% C2H3CN/60% 1H2O, acquired at 290 K and internally referenced to DSS, and extracts of the product ion mass spectrum of the ES/LC/MS/MS analysis of the partially reduced and alkylated 5LaaMII peptide. This material is available free of charge via the Internet at http://pubs.acs.org.

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