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Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of alpha-conotoxin MII.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2003 Mar 27; Vol. 46 (7), pp. 1266-72. - Publication Year :
- 2003
-
Abstract
- The alpha-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 alpha3beta2. 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. (1)H 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 alpha3beta2 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.
- Subjects :
- Amino Acid Sequence
Animals
Caco-2 Cells
Conotoxins chemistry
Conotoxins pharmacokinetics
Conotoxins toxicity
Ganglia, Parasympathetic cytology
Hemolysis
Humans
In Vitro Techniques
Magnetic Resonance Spectroscopy
Male
Molecular Sequence Data
Neurons drug effects
Neurons physiology
Nicotinic Antagonists chemistry
Nicotinic Antagonists pharmacokinetics
Nicotinic Antagonists toxicity
Patch-Clamp Techniques
Peptides, Cyclic chemistry
Peptides, Cyclic pharmacokinetics
Peptides, Cyclic toxicity
Permeability
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Receptors, Nicotinic drug effects
Receptors, Nicotinic physiology
Solubility
Structure-Activity Relationship
Conotoxins chemical synthesis
Lauric Acids chemistry
Nicotinic Antagonists chemical synthesis
Peptides, Cyclic chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 46
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12646037
- Full Text :
- https://doi.org/10.1021/jm020426j