Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug-binding sites. Based on this information, we rationally designed the parasite-specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species-specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much-needed, novel parasite inhibitors.

中文翻译：

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使用合理设计的抗微管蛋白剂抑制寄生虫增殖

由顶复门寄生虫引起的传染病仍然是全球公共卫生的威胁。微管蛋白中多个配体结合位点的存在使得该蛋白成为抗寄生虫药物发现的有吸引力的靶标。然而，尽管作为抗癌药物取得了显着的成功，但由于缺乏原生动物微管蛋白的结构和生化信息，原生动物寄生虫特异性微管蛋白药物的合理开发受到阻碍。在这里，我们展示了原生动物微管蛋白和微管的原子结构，并描绘了顶端复合微管蛋白药物结合位点的结构。基于这些信息，我们合理设计了寄生虫特异性微管蛋白抑制剂parabulin，并证明它可以抑制寄生虫的生长，同时对人体细胞没有影响。我们的工作首次提出了物种特异性微管蛋白药物的合理设计，提供了一个框架来利用人类和原生动物微管蛋白变体之间的结构差异，从而能够开发急需的新型寄生虫抑制剂。