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Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs

开发小分子代谢酶抑制剂作为广谱驱虫药

基本信息

批准号：
10370382
负责人：
James W Janetka
金额：
$ 78.83万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-11 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370382
关键词：
Active Sites Address Adult Affect Affinity Ancylostoma (genus)Animal Model Anthelmintics Area Basic Science Biochemical Biochemical Pathway Bioinformatics Biological Biological Assay Carnitine Clinical Consumption Crystallization Data Databases Development Docking Drug Design Drug Kinetics Drug Targeting Drug resistance Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Evaluation FRAP1 gene Formulation Funding Gene Expression Profiling Generations Genes Genome Genomics Goals Hamsters Homology Modeling Hookworms Human In Vitro Infection Intervention Intestines Knowledge Label Lead Life Maintenance Measures Metabolic Molecular Morbidity - disease rate Mus Necator americanus Nematoda Nematode infections Orthologous Gene Parasites Parasitic nematode Parasitology Pathway interactions Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Phylogeny Poverty Property Proteins Recombinants Research Rodent Model Roentgen Rays Series Structure Structure-Activity Relationship Systems Biology Taxonomy Techniques Testing Time Toxic effect Transferase Translational Research Trichuris United States National Institutes of Health Work base bioaccumulation burden of illness clinical candidate design drug development drug discovery experience human morbidity improved in vivo in vivo evaluation inhibitor innovation interdisciplinary approach knock-down lead optimization mortality multidisciplinary mutant novel novel therapeutics parasitism pathogen phosphoric diester hydrolase pre-clinical public health priorities rational design screening small molecule small molecule inhibitor small molecule therapeutics species difference

项目摘要

Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs Abstract Parasitic intestinal nematodes including hookworms, roundworm and whipworms, infect over two billion people worldwide, causing significant morbidity, perpetuation of poverty, and loss of life. Characterization of nematode genomes provides fundamental molecular information essential for accelerating basic and translational research, which is a public health priority due to the limited number of currently available effective drugs and increasing drug resistance. In this proposal, we will pursue post-genomic drug discovery studies to develop small molecule drugs as novel therapeutics to treat infections caused by these devastating parasites. We have established an extensive omics/bioinformatics database for human nematode parasites spanning the major taxonomic clades of Nematoda. Using systems biology and evolutionary principles, we reconstructed metabolic networks for 56 diverse nematode parasites and identified chokepoint enzymes, i.e. metabolic enzymes that uniquely consume a specific substrate or generate a unique product. This led to our central hypothesis that compounds that inhibit conserved chokepoint enzymes have a strong potential for broad control of diverse nematodes. To test this, we identified conserved targets and initial inhibitors with potential for broad-spectrum activity, for which phenotypic screening of parasites at the extremes of the phylogeny have validated our predictions. Furthermore, we established a unique database of nematode-specific molecular features among the chokepoint enzyme targets and experimentally established that active-site differences in the nematode enzymes relative to their human orthologs can rationally guide the design of selective inhibitors. The compounds with the best activity in our phenotypic screens are inhibitors predicted to target three known enzyme classes (CPT, mTOR/PI3K, and PDE). To confirm the putative nematode target(s), we will express nematode proteins and implement biochemical enzyme inhibition assays, employ affinity-based labeling techniques, and test for activity against target knockdown worms (Aim 1). By leveraging parasite-specific active- site features of the confirmed protein targets, we will use a X-ray structure-based drug design (SBDD) to optimize lead inhibitors of the three identified target classes (Aim 2). Optimized lead compounds most effective against the human hookworm Ancylostoma ceylanicum and the whipworm Trichuris muris in vitro will be tested in vivo for their pan-intestinal efficacy in hamster and mouse animal models of nematode infection (Aim 3). Our preliminary results, combined with this proposed research, are highly significant since they provide a better understanding of metabolic functions essential for nematode survival, which can be targeted for drug discovery. The rational targeting of metabolic chokepoint enzymes as anthelminthic agents is innovative, as is the concept of utilizing specific pan-phylum conserved targets to develop anthelmintic drug or drugs with broad spectrum efficacy against nematodes. Collectively, this work has high potential to provide one or more new small molecule therapeutics with broad spectrum activity against parasitic nematode infections.

开发小分子代谢酶抑制剂作为广谱驱虫药抽象的寄生肠道线虫，包括钩虫、蛔虫和鞭虫，感染超过 20 亿人在世界范围内造成严重的发病率、贫困的长期存在和生命的损失。线虫的表征基因组提供了加速基础和转化研究所必需的基本分子信息，由于目前可用的有效药物数量有限且不断增加，这是一个公共卫生优先事项耐药性。在本提案中，我们将进行后基因组药物发现研究以开发小分子药物作为治疗这些毁灭性寄生虫引起的感染的新疗法。我们建立了广泛的人类线虫寄生虫组学/生物信息学数据库跨越线虫纲的主要分类分支。利用系统生物学和进化原理，我们重建了 56 种不同线虫寄生虫的代谢网络并鉴定了阻塞点酶，即独特地消耗特定底物或产生独特产物的代谢酶。这导致了我们的中心假设是抑制保守性阻塞点酶的化合物具有广泛的应用潜力控制多种线虫。为了测试这一点，我们确定了具有潜力的保守靶标和初始抑制剂广谱活性，对系统发育极端的寄生虫进行表型筛选验证了我们的预测。此外，我们建立了一个独特的线虫特异性分子数据库阻塞点酶目标之间的特征，并通过实验确定了活性位点的差异线虫酶相对于其人类直系同源物的研究可以合理地指导选择性抑制剂的设计。在我们的表型筛选中具有最佳活性的化合物是预计针对三个目标的抑制剂已知的酶类别（CPT、mTOR/PI3K 和 PDE）。为了确认假定的线虫目标，我们将表达线虫蛋白并进行生化酶抑制测定，采用基于亲和力的标记技术，并测试针对目标击倒蠕虫的活性（目标 1）。通过利用寄生虫特异性活性对于已确认的蛋白质靶点的位点特征，我们将使用基于X射线结构的药物设计（SBDD）来优化三个已确定目标类别的先导抑制剂（目标 2）。优化的先导化合物最有效地对抗体外人类钩虫Ancylostoma ceylanicum和鞭虫Trichuris muris将在体内进行测试因其对线虫感染的仓鼠和小鼠动物模型的全肠道功效（目标 3）。我们的初步结果与这项拟议的研究相结合非常重要，因为它们提供了更好地了解线虫生存所必需的代谢功能，可以作为药物的靶点发现。将代谢阻塞点酶作为驱虫剂的合理靶向是创新的，利用特定的泛门保守靶标来开发驱虫药或具有广泛作用的药物的概念对线虫的谱效。总的来说，这项工作很有潜力提供一个或多个新的小型具有广谱抗寄生线虫感染活性的分子疗法。