Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutant proteins, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild-type transporters, as well as for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG^601,602AA and DAT-PG^584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperone in vivo in Drosophila harboring the DAT-PG^584,585AA mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutations.

中文翻译：

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Tropane-Based Ibogaine 类似物拯救折叠缺陷的血清素和多巴胺转运蛋白

导致蛋白质错误折叠的错义突变很少见，但总的来说，有缺陷的蛋白质折叠疾病是后果性的。折叠缺陷可以进行药理学校正（药物伴侣），但潜在的机制仍然是个谜。伊波加因碱及其活性代谢物降伊波加因碱纠正了多巴胺转运蛋白 (DAT) 中的折叠缺陷，但它们只能挽救数量非常有限的折叠缺陷 DAT 突变蛋白，这些蛋白会导致婴儿帕金森病和肌张力障碍。在此，通过重新配置复杂的伊波加因环系统并探索与野生型转运蛋白结合的结构要求，以及拯救两个等效的合成折叠缺陷突变体 SERT-PG ^601,602 AA 和 DAT-PG ，产生了一系列类似物^584,585AA。最活跃的托烷类类似物 ( 9b )在果蝇体内也是一种有效的药物^伴侣蛋白，其中含有 DAT-PG ^584,585 AA 突变，并在体外拯救了 13 种疾病相关的人类 DAT 突变蛋白中的 6 种。因此，已经确定了一种新的先导药物伴侣，它证明了携带 DAT 突变的患者的药物开发潜力。