Alessandro Gori, Ching-I A. Wang,Â Peta J. Harvey,Â K. Johan Rosengren,Â Rebecca F. Bhola,Â Maria L. Gelmi,Â Renato Longhi,Â Macdonald J. Christie,Â Richard J. Lewis,Â Paul F. Alewood,Â Andreas Brust, Ang, Chem. IEE, 2015, 54, 1361-4.
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 azideâ€“alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazoleâ€“disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4â€“Cys13 disulfide bond retained tertiary structure and full inâ€…vitro and inâ€…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.