title: Stabilization of the cysteine-rich conotoxin MrIA by using a 1,2,3-triazole as a disulfide bond mimetic.
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.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche via Mario Bianco 9, 20131 Milano (Italy).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gori
authors.forename: Ching-I A
authors.initials: CI
authors.lastname: Wang
authors.forename: Peta J
authors.initials: PJ
authors.lastname: Harvey
authors.forename: K Johan
authors.initials: KJ
authors.lastname: Rosengren
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Bhola
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gelmi
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Macdonald J
authors.initials: MJ
authors.lastname: Christie
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.forename: Andreas
authors.initials: A
authors.lastname: Brust
mesh_terms: D000595:Amino Acid Sequence; D057930:Click Chemistry; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D057786:Peptidomimetics; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D020916:Conotoxins; D004220:Disulfides; D050484:Norepinephrine Plasma Membrane Transport Proteins; D057786:Peptidomimetics; D014230:Triazoles; D003545:Cysteine
keywords: click chemistry; disulfide mimetics; drug design; peptidomimetics; structure-activity relationships