α-Conotoxin GI triazole-peptidomimetics: potent and stable blockers of a human acetylcholine receptor

Abstract

A conotoxin peptidomimetic was developed as a potential muscle relaxant that is highly potent and blood plasma stable.

α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

“…Cys3 is typically not modified in structure-activity relationship studies as it is a crucial residue in the Loop II disulfide bridge. In order to avoid disulfide isomerisation in the truncated Loop I Vc1.1 sequence, it is replaced with Ser without impacting activity; comparable inhibition of rat HVA Ca 2+ channels was noted by the authors for [1][2][3][4][5][6][7][8] [98]. This supports once again that the Loop II sequence plays a role in nAChR activity but is not solely responsible for activity at this target.…”

“…The 1,5-disubstituted isomer can be obtained via ruthenium(II)-catalysed azide-alkyne cycloaddition (RuAAC) [97]. The only reported triazole disulfide replacement in α-conotoxins was achieved in GI, where RuAAC was used to generate the 1,5-disubstituted-1,2,3-triazole replacement of the Loop I or Loop II bridge [98]. GI is a 13 residue α-conotoxin from the venom of Conus geographus that acts as a competitive antagonist for the muscular nAChR with excellent subtype specificity [99,100].…”

“…GI is a 13 residue α-conotoxin from the venom of Conus geographus that acts as a competitive antagonist for the muscular nAChR with excellent subtype specificity [99,100]. In vitro assessment at human nAChR indicated that the Loop I triazole analogue was devoid of activity while the Loop II triazole was slightly more active than native GI [98]. Whilst 1 H NMR spectroscopy was not used to assess the structures of these analogues, it is possible that the steric bulk of the triazole motif may disrupt the binding domain of the Loop I sequence, disrupt the conserved Loop I β-turn peptide structure through restricted flexibility and orientation, or fail to provide key disulfide receptor interactions.…”

Rationally Designed Peptidomimetics

“…[6] Two analogues of globular native α-GI were produced in which the two disulfide bonds were replaced in turn by the 1,5-triazole bridge designed previously. [7] The peptidomimetics were incubated with human muscle-type nAChRs and their activity determined in vitro by assessing antagonism of the nAChR mediated increase of [Ca 2+ ] in CN21 cells. One of the analogues 8, with the (Cys3-Cys13) disulfide bond replaced, retained full antagonist activity (IC 50 8.2 nM) compared to native α-GI 6 (IC 50 9.8 nM).…”

Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

“…Compounds 2 and 4,w hich present enhanced relative selectivity for AT 2 R, present similar NMR spectroscopic data, with respect to compounds 1 and 3 bearing lower AT 2 Rs electivity.T he enhanced number of cross-peaks between NH and TriH, recorded for compounds 2 and 4,c ould potentially indicate the formation of am ore compacts tructuralm icroenvironment driven by the triazole ring, with respect to compounds 1 and 3.T he observed compound stratification by NMRs pectroscopy is proportionate to the recorded AT 2 R/AT 1 Rs ubtypes electivity values. This could imply that the favorable stereo-electronic environment offered by the specific localization of the triazole rings [16] in compounds 2 and 4 could potentially be responsible for the recorded more favorable affinity for AT 2 R. Finally,b ased on the neuroprotectivef eatures associated by AT 2 R, we set to investigate the neurotrophica ction of our lead molecule, compound 2,a nd compare it with the established non-peptidea gonistc ompound 21 (C21), which has been reported to increase AT 2 R-mediated neuriteg rowth by Namsolleck et al, [17] (synthesis is briefly described in Figure S27 in the Supporting Information). Mouse embryonic cortical neurons exposed for 48 ht ot he proteolyticallys table compound 2 showedi ncreased neuriteg rowth,a ss hown in Figure 4.…”