Institut des Biomolécules Max Mousseron, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France.
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Nußbaumstraße 26, 80336 Munich, Germany.
J Med Chem. 2020 Nov 12;63(21):12682-12692. doi: 10.1021/acs.jmedchem.0c00957. Epub 2020 Oct 16.
Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3β2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the α3β2 neuronal nAChR subtype (IC 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3β2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic α3β2 nAChR subtype to the train-of-four fade.
毒液肽是很有前途的药物先导物，但它们的治疗用途通常受到稳定性和生物利用度问题的限制。在这项研究中，我们设计了α-芋螺毒素 CIA 的环状类似物，CIA 是一种强效的肌肉烟碱型乙酰胆碱受体（nAChR）阻断剂，对神经元 α3β2 亚型的亲和力显著降低。值得注意的是，所有类似物都保留了天然 CIA 对肌肉型 nAChR 的低纳摩尔活性，但在人血清中的降解稳定性显著提高，并且出人意料的是，对 α3β2 神经元 nAChR 亚型的效力提高了 52 倍（IC50 为 1.3 nM）。基于核磁共振衍生结构的比较揭示了一些可能解释在 α3β2 nAChR 中获得效力的差异。所有肽在注射到成年斑马鱼和应用于斑马鱼幼虫的浴液中时都具有高度的麻痹作用，这表明它们具有跨屏障能力和有效的摄取能力。最后，这些环状 CIA 类似物被证明是研究突触前 α3β2 nAChR 亚型对四串衰减的贡献的独特药理学工具。
