Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic

Gori, Alessandro, Wang, Ching-I A., Harvey, Peta J., Rosengren, K. Johan, Bhola, Rebecca F., Gelmi, Maria L., Longhi, Renato, Christie, Macdonald J., Lewis, Richard J., Alewood, Paul F. and Brust, Andreas (2015) Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic. Angewandte Chemie - International Edition, 54 4: 1361-1364. doi:10.1002/anie.201409678


Author Gori, Alessandro
Wang, Ching-I A.
Harvey, Peta J.
Rosengren, K. Johan
Bhola, Rebecca F.
Gelmi, Maria L.
Longhi, Renato
Christie, Macdonald J.
Lewis, Richard J.
Alewood, Paul F.
Brust, Andreas
Title Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic
Journal name Angewandte Chemie - International Edition   Check publisher's open access policy
ISSN 1433-7851
1521-3773
Publication date 2015
Year available 2014
Sub-type Article (original research)
DOI 10.1002/anie.201409678
Open Access Status
Volume 54
Issue 4
Start page 1361
End page 1364
Total pages 4
Place of publication Weinheim, Germany
Publisher Wiley-VCH Verlag
Collection year 2015
Language eng
Formatted abstract
The design of disulfide bond mimetics is an important strategy for optimising cysteine-rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4-disubstituted-1,2,3-triazole bridge, are described. Sequential copper-catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.
Keyword Click chemistry
Disulfide mimetics
Drug design
Peptidomimetics
Structure activity relationships
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 5 DEC 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
 
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