Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation.
Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation.
复制标题
蛋白酶作为抗疟疾靶标：遗传，化学和治疗验证的策略。
DOI：
10.1111/febs.14130
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Deu E
中科院分区：
文献类型：
--
作者：
Deu E
疟疾是一种毁灭性的寄生虫病，影响着世界上一半的人口。对新的抗疟疾药物，包括基于青蒿素的疗法，迅速出现耐药性，这使得开发具有新作用机制的药物变得迫在眉睫。蛋白酶是一种酶，由于我们对其酶机制和活性部位结构的了解，因此被证明非常适合靶向药物开发。更重要的是，疟原虫蛋白水解酶已被证明参与了寄生虫生存所必需的各种途径。然而，在抗疟疾药物开发领域，药理学方法而不是基于靶点的方法占据了主导地位，部分原因是在基因水平上强有力地确认疟原虫靶标的挑战。幸运的是，在过去的几年里，在开发高效的遗传方法来修改寄生虫方面取得了重大进展，包括几种有条件的方法。这一进展最终使我们不仅可以从基因上验证必要的基因，还可以研究它们的分子功能。在这篇综述中，我介绍了我们目前对蛋白酶在疟疾寄生虫生命周期中所起的生物学作用的理解。我还讨论了如何将疟原虫遗传学的最新进展、以蛋白酶为导向的化学生物学方法的改进以及以疟疾为重点的药理分析的发展结合起来，以实现对疟原虫蛋白酶作为可行药物靶点的强有力的生物、化学和治疗验证。
Malaria is a devastating parasitic disease affecting half of the world's population. The rapid emergence of resistance against new antimalarial drugs, including artemisinin‐based therapies, has made the development of drugs with novel mechanisms of action extremely urgent. Proteases are enzymes proven to be well suited for target‐based drug development due to our knowledge of their enzymatic mechanisms and active site structures. More importantly, Plasmodium proteases have been shown to be involved in a variety of pathways that are essential for parasite survival. However, pharmacological rather than target‐based approaches have dominated the field of antimalarial drug development, in part due to the challenge of robustly validating Plasmodium targets at the genetic level. Fortunately, over the last few years there has been significant progress in the development of efficient genetic methods to modify the parasite, including several conditional approaches. This progress is finally allowing us not only to validate essential genes genetically, but also to study their molecular functions. In this review, I present our current understanding of the biological role proteases play in the malaria parasite life cycle. I also discuss how the recent advances in Plasmodium genetics, the improvement of protease‐oriented chemical biology approaches, and the development of malaria‐focused pharmacological assays, can be combined to achieve a robust biological, chemical and therapeutic validation of Plasmodium proteases as viable drug targets.
登录
查看更多内容
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
加工恶性疟原虫梅罗唑群体表面蛋白MSP1激活谱线结合功能，从而使RBC的寄生虫出口。
影响因子：
30.3
作者：
Das S;Hertrich N;Perrin AJ;Withers-Martinez C;Collins CR;Jones ML;Watermeyer JM;Fobes ET;Martin SR;Saibil HR;Wright GJ;Treeck M;Epp C;Blackman MJ
通讯作者：
Blackman MJ
影响因子：
9
作者：
通讯作者：
--
影响因子：
6.7
作者：
Baker RP;Wijetilaka R;Urban S
通讯作者：
Urban S
影响因子：
6.7
作者：
Collins CR;Hackett F;Strath M;Penzo M;Withers-Martinez C;Baker DA;Blackman MJ
通讯作者：
Blackman MJ