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Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of α-conotoxin MII

Journal Article


Abstract


  • 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.

UOW Authors


  •   Blanchfield, Joanne T. (external author)
  •   Dutton, Julie L. (external author)
  •   Hogg, Ron C. (external author)
  •   Gallagher, Oliver P. (external author)
  •   Craik, David J. (external author)
  •   Jones, Alun (external author)
  •   Adams, David
  •   Lewis, Richard J. (external author)
  •   Alewood, Paul F. (external author)
  •   Toth, Istvan (external author)

Publication Date


  • 2003

Citation


  • Blanchfield, J. T., Dutton, J. L., Hogg, R. C., Gallagher, O. P., Craik, D. J., Jones, A., Adams, D. J., Lewis, R. J., Alewood, P. F. & Toth, I. (2003). Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of α-conotoxin MII. Journal of Medicinal Chemistry, 46 (7), 1266-1272.

Scopus Eid


  • 2-s2.0-0344406263

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/688

Number Of Pages


  • 6

Start Page


  • 1266

End Page


  • 1272

Volume


  • 46

Issue


  • 7

Abstract


  • 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.

UOW Authors


  •   Blanchfield, Joanne T. (external author)
  •   Dutton, Julie L. (external author)
  •   Hogg, Ron C. (external author)
  •   Gallagher, Oliver P. (external author)
  •   Craik, David J. (external author)
  •   Jones, Alun (external author)
  •   Adams, David
  •   Lewis, Richard J. (external author)
  •   Alewood, Paul F. (external author)
  •   Toth, Istvan (external author)

Publication Date


  • 2003

Citation


  • Blanchfield, J. T., Dutton, J. L., Hogg, R. C., Gallagher, O. P., Craik, D. J., Jones, A., Adams, D. J., Lewis, R. J., Alewood, P. F. & Toth, I. (2003). Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of α-conotoxin MII. Journal of Medicinal Chemistry, 46 (7), 1266-1272.

Scopus Eid


  • 2-s2.0-0344406263

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/688

Number Of Pages


  • 6

Start Page


  • 1266

End Page


  • 1272

Volume


  • 46

Issue


  • 7