Discovery of new molecular phenotypes for anti-schistosomal drug screening

抗血吸虫药物筛选新分子表型的发现

基本信息

批准号：
10039280
负责人：
John D Chan
金额：
$ 22.08万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039280
关键词：
Address Alternative Therapies Animals Anthelmintics Antiparasitic Agents Apoptosis Biological Assay Biology Chemicals Clinical Combined Modality Therapy Data Descriptor Development Disease Drug Combinations Drug Exposure Drug Screening Drug resistance Drug usage Event Exposure to Future Gene Expression Profile Gene Expression Profiling Genes Genetic Transcription Genetic Variation Germ Cells Global Change Goals Harvest In Situ Hybridization In Vitro Infection Lead Liver Measurement Measures Mesentery Metabolism Mitosis Molecular Morphology Movement Mus Muscle Nail plate Outcome Parasites Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phenotype Plasmodium Platyhelminths Praziquantel Praziquantel resistance Reporting Research Resistance Schistosoma Schistosomatidae Schistosomiasis Tissues Transcript Treatment Failure Work base combat comparative design differential expression drug action drug discovery drug efficacy drug mechanism druggable target improved in vitro Assay in vivo innovation insight molecular phenotype motor impairment neglect neglected tropical diseases novel novel therapeutics prevent response risk minimization screening transcriptome sequencing

项目摘要

PROJECT SUMMARY: Parasitic Schistosoma blood flukes cause the neglected topical disease schistosomiasis. This disease infects >200 million people but is clinically treated by monotherapy with just one broad spectrum drug, praziquantel (PZQ). The vast scope of the disease and the prospect of PZQ resistance highlight the need for alternative therapies. Indeed, PZQ treatment failure has been reported in the field and resistance can be selected in the lab, indicating that standing genetic variation for resistance already exists. However, drug discovery efforts are hampered by our poor understanding of how existing anti-schistosomal drugs work. Many of these older compounds were discovered >40 years ago using in vivo animal screens. The long-term goal is to identify druggable targets / lead compounds to treat schistosomiasis. The overall objective of this application is to resolve the molecular changes in schistosome biology that underpin the efficacy of existing anti-schistosomal compounds, moving beyond superficial descriptors of worm morphology towards quantitative endpoints that can be assayed for new leads. The central hypothesis is that anthelmintics evoke molecular changes that are more productive screening endpoints than superficial phenotypes. The rationale for this project is that current schistosomiasis drug discovery efforts often focus on in vitro assays for changes in movement or morphology, which are poor predictors of efficacy in vivo. Some anti-schistosomal drugs do cause changes in worm movement / morphology, but others are efficacious in vivo with no effect on movement in vitro, and still other drugs impair movement in vitro but are ineffective in vivo. Better predictors of anti- parasitic action are needed to develop more productive assays. We will pursue two specific aims: (1) Profiling the activity of 10 chemically diverse anti-schistosomal drugs using a panel of molecular assays and (2) Identifying transcriptional signatures of anthelmintics with distinct mechanisms of action. The first aim will resolve mechanistic similarities and differences between these 10 anthelmintics by systematically assessing cellular and molecular changes in worms exposed to drug in vivo. These outcomes will serve as endpoints for the development of quantitative assays for future screens. The second aim will compare the transcriptional responses of parasites to each drug, providing an unbiased readout of global changes to schistosome biology and allowing drugs to be binned according to putative mechanisms of action. Insight into the comparative mechanisms of anti-schistosomal compounds will allow us to rationally select alternative drugs in the event of PZQ treatment failure. This information will also inform drug-combination strategies to prevent the emergence of drug resistance. The research proposed in this application is significant because it will provide new assays for future drug discovery efforts that are better predictors of in vivo anti-parasitic efficacy than existing superficial phenotypes of worm movement and morphology. This research is innovative because it is will establish mechanism-based assays to identify PZQ-alternatives to combat and prevent drug resistance.

项目摘要：寄生血吸虫血液漏气引起被忽视的局部疾病血吸虫病。这种疾病感染了2亿人广谱药物，praziquantel（PZQ）。疾病的广泛范围和PZQ抗性的前景强调需要替代疗法。实际上，该领域已经报道了PZQ治疗失败可以在实验室中选择电阻，表明抗药性的遗传差异已经存在。但是，我们对现有抗距离的毒素的理解不佳，阻碍了药物发现的努力毒品工作。这些较旧的化合物中的许多是在40年前使用体内动物筛选发现的。这长期目标是鉴定可药物靶 /铅化合物来治疗血吸虫病。总体目标该应用的是解决基础的血块生物学分子变化现有的抗速溶体化合物，超越了蠕虫形态的表面描述符可以分析新线索的定量端点。中心假设是驱虫学唤起了分子变化比浅表表型更有生产力筛选终点。理由该项目是当前的血吸虫病药物发现工作通常集中于体外测定法运动或形态学，它们是体内功效的预测指标。一些抗固定体药物导致蠕虫运动 /形态的变化，但其他人在体内有效，对运动没有影响体外，其他药物在体外会损害运动，但在体内无效。更好地预测抗需要寄生作用来开发更有生产力的测定。我们将追求两个具体目标：（1）分析使用一组分子测定法和（2）识别具有不同作用机制的驱虫药的转录特征。第一个目标通过系统评估，解决这10种驱虫药之间的机械相似性和差异在体内暴露于药物的蠕虫中的细胞和分子变化。这些结果将作为终点开发未来屏幕的定量测定法。第二个目标将比较转录寄生虫对每种药物的反应，提供了对整体生物学的全球变化的公正读数并允许根据推定的作用机理对药物进行归类。洞悉比较抗固定体化合物的机制将使我们能够合理选择替代药物 PZQ治疗失败。该信息还将为防止出现的药物组合策略提供信息耐药性。本应用程序中提出的研究很重要，因为它将提供新的测定对于未来的药物发现努力，它比现有的更好地预测体内抗寄生虫功效蠕虫运动和形态的表面表型。这项研究具有创新性，因为它将建立基于机制的测定法，以识别PZQ-抗药性以对抗和防止耐药性。