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

恶性疟原虫（导致疟疾）和刚地弓形虫（导致弓形虫病）等寄生生物引起广泛的疾病和发病率，需要新的抗寄生虫药物来应对对目前使用的所有抗寄生虫疗法的耐药性普遍上升的问题。这两种寄生虫的有效靶点是细胞色素bc1复合体，这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。该项目的目的是通过解决弓形虫bc1结构，将我们现有的牛bc1结构知识转化为寄生虫来源的细胞色素bc1系统。这将主要用于设计新的有效和选择性的原生动物抑制剂，但也将有助于利兹大学开发的现有化合物系列的进步。这将提供一种混合技术，这将是一种强有力的方法，可以充分表征抑制剂与bc1的结合，并开发一系列更有效的抑制剂。通过现有的合作者（Rima McLeod教授，芝加哥大学），我们也有机会获得代表各种生命周期形式的弓形虫菌株，这将使我们能够确定我们的小分子bc1抑制剂作为抗寄生虫药物的潜力。学生将学习先进的基于结构的分子设计，合成有机/药物化学，以及晶体学，生化和生物物理方法，并使用最先进的同步加速器源，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精神，鼓励打破传统的学科障碍，鼓励发展研究小组的专题网络。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（利兹的两位导师都是成员），学生将被嵌入一个环境中，在上述所有领域提供强大的具体培训，以及一个完善的研究生培训计划，旨在提高更广泛的技能。利物浦综合生物学研究所（IIB）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技术相结合方面取得了巨大成功，也反映了这种研究生培训方法。结构生物学是一个跨领域的活动，它连接了学院的几个研究所，并与药物化学家和世界著名的利物浦热带医学院合作

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