The potency and selectivity of conotoxin peptides for neuropathic receptors has made them attractive lead compounds in the development of new therapeutics. Specifically, α-conotoxin GI has been shown to be an unparalleled antagonist of the nicotinic acetylcholine receptor (nAChR). However, as with other peptidic leads, poor protease resistance and the redox instability of the conotoxin scaffold limit bioactivity. To counter this, we have employed the underutilised 1,5-disubstituted 1,2,3-triazole to act as a structural surrogate of the native disulfide bonds. Using an efficient, on-resin ruthenium azide-alkyne cycloaddition (RuAAC), each disulfide bond was replaced in turn and the biological activities quantified. One of the mimetic isomers exhibited a comparable activity to the native toxin, while the other showed no biological effect. The active mimetic isomer 11 was an order of magnitude more stable in plasma than the native GI. The NMR solution structure of the mimetic overlays extremely well with the structure for the native GI demonstrating that the triazole bridge is an exceptional surrogate for the disulfide bridge. Development of this potent and stable mimetic of GI leads us to believe that this strategy will yield many other new conotoxin-inspired probes and therapeutics.

中文翻译：

---

α-ConotoxinGI三唑拟肽：一种有效且稳定的人乙酰胆碱受体阻滞剂† ‡

芋螺毒素肽对神经病性受体的效力和选择性使其成为新疗法开发中的诱人先导化合物。具体而言，已证明α-芋螺毒素GI是烟碱乙酰胆碱受体（nAChR）的无与伦比的拮抗剂。然而，与其他肽前导一样，蛋白酶抗性差和芋螺毒素支架的氧化还原不稳定性限制了生物活性。为了解决这个问题，我们采用了未充分利用的1,5-二取代1,2,3-三唑作为天然二硫键的结构替代物。使用高效的树脂上叠氮化钌-炔烃环加成（RuAAC），依次替换每个二硫键，并对生物活性进行定量。一种模拟异构体表现出与天然毒素相当的活性，而另一种则没有生物学作用。11在血浆中比天然GI更稳定一个数量级。模拟物的NMR溶液结构与天然GI的结构重叠得非常好，表明三唑桥是二硫桥的特殊替代物。这种有效且稳定的GI模拟物的开发使我们相信，这种策略将产生许多其他受到芋螺毒素启发的新探针和治疗剂。