Synthesis and In vitro Biological Activity of Cyclic Lipophilic [chi]-Conotoxin MrIA Analogues

• Published in: International journal of peptide research and therapeutics Vol. 13; no. 1-2; p. 307
• Main Authors: Dekan, Zoltan, Paczkowski, Filip A, Lewis, Richard J, Alewood, Paul F
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Nature B.V 01-06-2007
• Subjects: Peptides; Proteins
• ISSN: 1573-3149; 1573-3904
• DOI: 10.1007/s10989-007-9083-2

Issue Title: Bruce Merrifield Commemorative Issue 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 Boc chemistry and N- to C-cyclic analogues accessed by cysteine-mediated intramolecular native chemical ligation. In vitro biological activity at the human NET was evaluated by functional assays. All analogues inhibited the uptake of [^sup 3^H]noradrenaline with comparable potencies to that of the native peptide, with one of the analogues, the linear N-terminal aminotetradecanoyl MrIA showing a 3-fold increase in potency (p < 0.05).[PUBLICATION ABSTRACT]