Structure-based design of new Cytochrome bc1 inhibitors to combat parasitic infections

基于结构的新型细胞色素 bc1 抑制剂对抗寄生虫感染的设计

• 批准号: 1941966
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1941966
• 关键词: Structure; based; design; new; Cytochrome

Parasitic organisms such as Plasmodium falciparum- responsible for malaria, and Toxoplasma gondii- responsible for toxoplasmosis, cause widespread disease and morbidity, and new antiparasitic drugs are needed to combat the general rise in resistance to all currently used antiparasitic therapies. A validated target in both of these parasites is the cytochrome bc1 complex, which is a key mitochondrial enzyme that catalyses the transfer of electrons in order to maintain the membrane potential of mitochondria. The aim of this project is to translate our existing structural knowledge of bovine bc1 to the parasite-derived cytochrome bc1 system by solving the first ever Toxoplasma bc1 structure. This will be used to primarily design new potent and selective protozoan inhibitors but will also contribute to the advancement of existing compound series in development at Leeds. This will provide a mix of techniques which will be a powerful approach to fully characterising inhibitor binding to bc1 and developing a series of more potent inhibitors.Via existing collaborators (Prof. Rima McLeod, University of Chicago), we also have access to T. gondii strains represting various life cycle forms, which will enable us to establish the potential of our small molecule bc1 inhibitors as antiparasitic drug leads.The student will be trained in advanced structure-based molecular design, synthetic organic/medicinal chemistry, as well as crystallographic, biochemical and biophysical methods and use the most advance Synchrotron sources like DIAMOND, SOLEIL and SPRING-8 for experiments. The research environments in both of the collaborating institutions provides an ethos that encourages the breaking down of traditional disciplinary barriers and encourages the development of thematic networks of research groups. At Leeds, this approach is a central feature within the world-leading Astbury Centre for Structural Molecular Biology (both Leeds supervisors are members) and the student will be embedded within an environment that offers robust specific training in all of the above areas in addition to a well-developed postgraduate training programme designed to enhance a broader range of skills. This approach to postgraduate training is mirrored within the Institute of Integrative Biology (IIB) at Liverpool which has been highly successful in integrating evolutionary biology with genomic and proteomic technologies, environmental biology with post-genomics and clinical microbiology. Structural Biology is a cross-cutting activity that bridges several institutes of the Faculty as well as having engaging programmes with medicinal chemists and the world renowned Liverpool School of Tropical Medicine

寄生生物体，如恶性疟原虫-负责疟疾，弓形虫-负责弓形虫病，引起广泛的疾病和发病率，需要新的抗寄生虫药物来对抗目前使用的抗寄生虫疗法的耐药性普遍上升。在这两种寄生虫中，一个经过验证的靶点是细胞色素bc 1复合物，它是一种关键的线粒体酶，催化电子转移以维持线粒体的膜电位。本项目的目的是通过解决第一个弓形虫bc 1结构，将我们现有的牛bc 1结构知识转化为寄生虫衍生的细胞色素bc 1系统。这将主要用于设计新的有效的和选择性的原生动物抑制剂，但也将有助于在利兹开发现有的化合物系列的进步。通过现有的合作者（芝加哥大学Rima McLeod教授），我们还可以获得T.本课程将对学生进行基于结构的分子设计、合成有机/药物化学、晶体学、生物化学和生物物理学方法的培训，并使用最先进的同步辐射源如DIAMOND、SOLEIL和SPRING-8进行实验。这两个合作机构的研究环境提供了一种鼓励打破传统学科障碍并鼓励发展研究小组专题网络的风气。在利兹，这种方法是世界领先的阿斯特伯里结构分子生物学中心的核心特征（利兹的两名主管都是成员），学生将被嵌入到一个提供所有上述领域强大的具体培训的环境中，此外还有一个完善的研究生培训计划，旨在提高更广泛的技能。这种研究生培训方法反映在利物浦的综合生物学研究所（IIB）中，该研究所在将进化生物学与基因组学和蛋白质组学技术，环境生物学与后基因组学和临床微生物学相结合方面非常成功。结构生物学是一个跨学科的活动，连接学院的几个研究所，并与药物化学家和世界著名的利物浦热带医学学院进行合作