Novel Therapeutics for Treatment of River Blindness and Lymphatic Filariasis

治疗河盲症和淋巴丝虫病的新疗法

基本信息

批准号：
9222644
负责人：
Judy Sakanari
金额：
$ 26.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-26 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222644
关键词：
Adult Affect Animal Model Binding Biochemical Pathway Biological Biological Assay Brugia Cattle Chemicals Developing Countries Development Disease Drug Targeting Drug usage Effectiveness Enzymes Evaluation Filarial Elephantiases Formulation Future Gerbils Goals Growth Helminth Proteins In Vitro Infection International Lead Mass Spectrum Analysis Measures Metabolic Pathway Methods Modeling Modification Molecular Nematoda Ocular Onchocerciasis Onchocerca Onchocerciasis Organism Outcome Parasites Parasitic nematode Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Protein Family Proteins Proteomics RNA Interference Research Personnel Role Structure-Activity Relationship Testing Vaccines analog design differential expression drug distribution genome-wide improved in vitro Assay in vivo inhibitor/antagonist innovation killings life history nanomolar neglect new technology novel novel therapeutics pre-clinical programs scaffold screening tool

项目摘要

PROJECT SUMMARY/ABSTRACT River blindness (onchocerciasis) and lymphatic filariasis are two major neglected diseases caused by parasitic nematodes that together affect an estimated 145 million people worldwide in mostly poor, developing countries. To date, there are no vaccines for these diseases and there are no drugs that are effective against the adult stages (macrofilariae) and amenable for mass drug distribution to eliminate these diseases. The overall goal of our project is to identify macrofilaricidal lead candidates for the treatment of river blindness and lymphatic filariasis. There is a critical need for safe, effective macrofilaricidal drugs for use in mass drug administration and test and treat settings to support international control programs working towards the goal of eliminating these diseases. Recently, we identified a potent compound that is effective in killing both adult Onchocerca and Brugia worms in the nanomolar range in vitro. We hypothesize that THP will be an effective macrofilaricide in our newly developed animal models of infection and that THP will significantly decrease worm burden in both of these infections. We have already synthesized analogs that might be even more potent in our in vitro screening assays and consequently in vivo. We further propose to identify THP target(s) in adult Onchocerca and Brugia using an innovative chemical-proteomic approach referred to as thermal shift (TS) profiling. By identifying the target(s) of our chemical probes, we may elucidate novel biological pathway(s) that are essential and relevant to other nematode parasites and pathogenic organisms. In the R33 phase, we will optimize the potency of THP and its analogs utilizing iterative cycles of chemical design and synthesis along with in vitro and in vivo evaluation. We will also use the thermal shift assay to confirm that these newly synthesized compounds are acting at the same target(s) identified in the R21 phase. Predicted targets identified from the TS assays with Brugia and Onchocerca worm lysates will be evaluated by RNAi to assess their essential functions during worm development and for survival. By the end of the R33, we will have identified 1-2 lead candidates and evaluated the drug targets in functional worm assays. Future directions will include further refinement of the 1-2 preclinical candidates in late phase lead optimization and formulation studies, followed by animal models of lymphatic filariasis (Brugia/gerbil infection) and the cow model of onchocerciasis to validate potency and efficacy as macrofilaricides.

项目摘要/摘要河流失明（Onchocerciasis）和淋巴丝虫病是由两种主要被忽视的疾病寄生的线虫共同影响了全球估计有1.45亿人的大多数贫困人口国家。迄今为止，没有针对这些疾病的疫苗，也没有有效的药物成人阶段（大型脂肪菌），可用于消除这些疾病的大规模药物分布。这我们项目的总体目标是确定用于治疗河流和河流的大写铅候选者淋巴丝虫病。至关重要的需要安全，有效的大写药物用于大众药物管理和测试和处理设置，以支持国际控制计划的目标消除这些疾病。最近，我们确定了一种有效杀死成人OnChocerca和Brugia的有效化合物体外纳摩尔范围的蠕虫。我们假设THP在我们的新开发的感染动物模型，THP将大大减轻蠕虫负担这些感染。我们已经合成了在体外筛查中可能更有效的类似物测定，因此体内。我们进一步建议确定成人OnChocerca和Brugia中的THP目标使用创新的化学蛋白质方法方法，称为热移（TS）分析。通过识别我们的化学探针的靶标，我们可以阐明必不可少的新型生物学途径到其他线虫寄生虫和致病生物。在R33阶段，我们将利用迭代周期的THP及其类似物的效力优化化学设计和合成以及体外和体内评估。我们还将使用热移测定确认这些新合成的化合物在R21中确定的相同靶标作用阶段。通过Brugia和OnChocerca蠕虫裂解物从TS测定中确定的预测目标将是通过RNAi评估以评估其在蠕虫发育和生存过程中的基本功能。到结束 R33，我们将确定1-2位铅候选者，并评估功能性蠕虫测定中的药物靶标。未来的方向将包括在后期铅中进一步改进1-2个临床前候选人优化和制剂研究，然后进行淋巴丝虫病的动物模型（Brugia/Gerbil感染）以及牛的牛模型，以验证效力和效力为大氟酸酯。