Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Science. 2017 Mar 31;355(6332):1416-1420. doi: 10.1126/science.aal1807.
The parasitic protists of the genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.
属于的寄生虫原生动物感染人类和家畜，导致严重的死亡率和巨大的经济损失。威胁最大的锥虫病是恰加斯病，影响了美洲多达 1200 万人。我们报告了一种通过阻断糖体/过氧化物酶体导入来选择性杀死的方法，该方法依赖于 PEX14-PEX5 蛋白-蛋白相互作用。我们开发了能够有效破坏 PEX14-PEX5 相互作用的小分子。这导致糖体酶的定位错误，引起代谢灾难，并杀死寄生虫。高分辨率 X 射线结构和核磁共振数据使抑制剂的有效设计成为可能，其具有与已批准药物相当的杀锥虫活性。这些结果确定 PEX14 是 的“阿喀琉斯之踵”，适合开发针对锥虫病的新疗法，并为其开发提供了结构基础。
