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Nature:抵御耐药性疟疾新型疗法的开发再获突破!

2016年02月16日 浏览量: 评论(0) 来源:生物谷 作者:生物谷 责任编辑:admin
摘要:近日,刊登在国际杂志Nature上的一项研究论文中,来自斯坦福大学等多个研究机构的科学家通过联合研究,使用尖端技术设计出了一种可以有效抵御疟疾的智能药物。蚊子传播的疟疾每年在全球会引发45万儿童死亡,而最早开发与中亚的可以有效抵御疟疾的药物青蒿素的使用也使得很多疟原虫产生了耐药性,在短短5年内对青蒿素耐药性的疟原虫已经扩散到了6个国家。

研究者Tilley表示,青蒿素可以促进疟原虫机体的蛋白损伤,但疟原虫常常会开发出一种特殊的方式来处理这种损伤,因此抵御耐药性疟原虫的新型药物的开发迫在眉睫;

文章中研究者开发的新型药物可以靶向作用疟原虫的废弃物处理系统,即为蛋白酶体系统,疟原虫的蛋白酶体系统类似于一个撕碎机,其会嚼碎损伤或耗尽的蛋白质;而且当疟原虫从一个生命阶段过渡到另一个阶段后期会产生大量损伤的蛋白,这些蛋白非常依赖蛋白酶体系统,而其或许也可以作为新型的药物靶点来帮助开发新型抗疟疾药物。

斯坦福大学的研究者纯化了疟原虫的蛋白酶体,并且利用新型的方法检测了蛋白酶体消解多种不同肽类序列的活性,随后他们设计出了一种可以选择性靶向抑制疟原虫蛋白酶体的新型抑制剂;随后来自剑桥医学研究委员会(MRC)的研究者利用一种名为单颗粒低温电子显微技术产生了一种三维高分辨率的蛋白结构,这可以帮助进一步设计抵御耐药性疟原虫的靶向药物。 研究者指出,这种新型的蛋白酶体抑制剂实际上可以补充青蒿素的治疗,青蒿素引发蛋白质损伤,而蛋白酶体抑制剂抑制疟原虫对损伤蛋白质进行修复,这种二合一的疗法或许会对疟原虫进行双重打击,进而提高青蒿素的效果,恢复期抵御耐药性疟原虫的能力。

下一步研究者计划对武田制药(制药公司)的文库进行筛选来寻找不影响人类蛋白酶体的类似药物,当前的蛋白酶体抑制剂或许是一个很好的开端,但却并不适用于人类,而后期进入到人类可以口服或许还需要一段很长的时间;研究者表示,如果可以在武田公司的文库中找到一种可以和新型疟疾药物匹配的药物,那么或许就可以很快进行人类机体的临床试验了。

原文摘要:Structure- and function-based design of Plasmodium-selective proteasome inhibitors Hao Li, Anthony J. O’Donoghue, Wouter A. van der Linden, Stanley C. Xie, Euna Yoo, Ian T. Foe, Leann Tilley, Charles S. Craik, Paula C. A. da Fonseca & Matthew Bogyo The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation1. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle2, 3, 4, 5. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents2, 6. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials7, 8, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents.

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