Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.
Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.
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DOI：
10.15252/emmm.202013818
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发表时间：
2021-11-08
影响因子：
11.1
通讯作者：
Steinmetz MO
中科院分区：
文献类型：
--
作者：
Gaillard N;Sharma A;Abbaali I;Liu T;Shilliday F;Cook AD;Ehrhard V;Bangera M;Roberts AJ;Moores CA;Morrissette N;Steinmetz MO
由顶复门寄生虫引起的传染病仍然是全球公共卫生威胁。微管蛋白中多个配体结合位点的存在使这种蛋白质成为抗寄生虫药物发现的有吸引力的靶标。然而，尽管作为抗癌剂取得了显著的成功，但原生动物寄生虫特异性微管蛋白药物的合理开发受到缺乏原生动物微管蛋白结构和生化信息的阻碍。在这里，我们提出了原生动物微管蛋白和微管的原子结构，并描绘了apicomplexan微管蛋白药物结合位点的结构。基于这些信息，我们合理地设计了寄生虫特异性微管蛋白抑制剂parabulin，并表明它抑制寄生虫的生长，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，以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。为了发现靶向独特寄生虫蛋白和途径的新型药物支架，使用结构指导的合理药物设计实现了寄生虫微管蛋白的特异性抑制。
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. In an effort to discover novel drug‐scaffolds targeting unique parasite proteins and pathways, specific inhibition of parasite tubulin was achieved using structure‐guided rational drug design.