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Neuroscience

C&EN 中文版

消灭亨廷顿氏病蛋白

研究人员筛选了3,000多种化合物，发现了可清除亨廷顿蛋白突变体的小分子

by Laura Howes
October 31, 2019 | A version of this story appeared in Volume 97, Issue 43
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中国和英国的研究人员发现了几种小分子，能结合并帮助清除导致亨廷顿氏病的蛋白。研究人员表示，这一发现可能是实现该疾病治疗的重要一步（Nature 2019, DOI: 10.1038/s41586-019-1722-1)。

The structure of one of the lead compounds in the study.

亨廷顿氏病是一种致命的遗传疾病。病因是突变形成亨廷顿蛋白变异体，其中很大一部分是由氨基酸谷氨酰胺组成。当这种蛋白质错误折叠时，它会在神经元中聚集，最终导致神经细胞降解并死亡。

复旦大学的鲁伯埙及同事和普利茅斯大学的合作者们想找到一种治疗方法，以帮助神经元清除这种有害的突变蛋白。他们筛选了3,000多种与变异亨廷顿蛋白（mHTT ）和LC3B 相互作用的化合物，后者与蛋白质清除有关。找到两种目标小分子后，他们又寻找类似的化合物，并测试了它们的活性。其先导化合物降低了人类神经元细胞培养物中的mHTT 水平，并改变了小鼠和果蝇模型中的亨廷顿氏病症状。研究人员还通过显微镜在自噬体中发现了与化合物结合的蛋白质，该结构可降解蛋白质。

Hilal Lashuel 说，开发能选择性结合并清除mHTT的小分子会是一项重大进展，他在洛桑瑞士联邦理工学院（EPFL）致力于研究神经退行性疾病中的蛋白质错误折叠。但是，Lashuel指出，这项研究并未探讨这些化合物特异性的结构基础，也没有探讨它们如何连接两种蛋白质。

鲁伯埙表示，他认为这些化合物为亨廷顿氏病的治疗提供了切入点。同时，Lashuel 说，并没有看到他感兴趣的一些细节。幸运的是，由鲁伯埙和团队测试的化合物可以在市场上买到。Lashuel 说，他的团队已经订购了这些化合物，因为他们看到了潜力，并计划更详细地研究该机理。.

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