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- Title
Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic.
- Authors
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
- 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.
- Subjects
CYSTEINE; CONOTOXINS; TRIAZOLES; DISULFIDES; RING formation (Chemistry); PLASMA stability
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 4, p1361
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201409678