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Stabilization of the Cysteine‐Rich Conotoxin MrIA by Using a 1,2,3‐Triazole as a Disulfide Bond Mimetic
Author(s) -
Gori Alessandro,
Wang ChingI 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
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201409678
Subject(s) - chemistry , click chemistry , triazole , combinatorial chemistry , cysteine , cycloaddition , disulfide bond , regioselectivity , conotoxin , stereochemistry , peptide , organic chemistry , biochemistry , enzyme , catalysis
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.