Synthesis and In vitro Biological Activity of Cyclic Lipophilic χ-Conotoxin MrIA Analogues

@article{Dekan2007SynthesisAI,
  title={Synthesis and In vitro Biological Activity of Cyclic Lipophilic $\chi$-Conotoxin MrIA Analogues},
  author={Zoltan Dekan and Filip A. Paczkowski and Richard James Lewis and Paul F. Alewood},
  journal={International Journal of Peptide Research and Therapeutics},
  year={2007},
  volume={13},
  pages={307-312}
}
The 13-residue peptide, χ-conotoxin MrIA extracted from the venom of Conus marmoreus, is a potent and selective inhibitor of the human noradrenaline transporter (NET). With the aim of improving its biophysical properties, chemical modifications were performed including the attachment of a lipophilic amino acid at the N-terminus and cyclisation of the peptide backbone with functionality introduced into the linker. All χ-conotoxin MrIA analogues were assembled on solid phase by highly optimised… 

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References

SHOWING 1-10 OF 17 REFERENCES
Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of alpha-conotoxin MII.
TLDR
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.
Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter.
TLDR
It is shown that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET, which represents a new topology among a growing number of circular disulfide-rich peptides.
Conotoxins and their potential pharmaceutical applications
The neurotoxins isolated from cone shell venoms are a diverse group of small, disulfide‐rich peptides. Most of the active peptides isolated to date have been shown to specifically target various
Two new classes of conopeptides inhibit the α1-adrenoceptor and noradrenaline transporter
TLDR
Two new classes of conopeptides are discovered that act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.
Anti-allodynic efficacy of the χ-conopeptide, Xen2174, in rats with neuropathic pain
TLDR
Xen2174 appears to be a promising candidate for development as a novel therapeutic for i.t. administration to patients with persistent neuropathic pain, after confirming the noradrenergic mechanism of action.
Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure-activity relationship.
TLDR
The inhibitory effect of chi-MrIA was found to be dependent on Na+ with the conopeptide becoming a less effective blocker of [3H]norepinephrine by the NET under the conditions of reduced extracellular Na+, similar to the antidepressant inhibitors of the NET.
Converting a peptide into a drug: strategies to improve stability and bioavailability.
TLDR
Different experimental approaches to transforming a peptide into a potential drug are described and examples of the usefulness of these strategies are provided.
THIA ZIP REACTION FOR SYNTHESIS OF LARGE CYCLIC PEPTIDES : MECHANISMS AND APPLICATIONS
This paper describes the mechanism and application of an efficient thia zip cyclization that involves a series of intramolecular rearrangements in a cysteine-rich peptide for the synthesis of large
χ-Conopeptide MrIA Partially Overlaps Desipramine and Cocaine Binding Sites on the Human Norepinephrine Transporter*
TLDR
A comparison of the results with previous data for desipramine and cocaine inhibition of norepinephrine uptake by the mutant hNETs reveals that MrIA binding to hNET occurs at a site that is distinct from but overlaps with the binding sites for tricyclic antidepressants and cocaine.
Oral absorption of lipidic amino acid conjugates
Abstract A series of unlabelled and radiolabelled lipidic peptide conjugates 2a-2f were synthesised by reduction of 1a-1f with NaBH 4 and NaB 3 H 4 , respectively. Initial in vitro experiments using
...
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