Cholinergic Receptors as Targets for Accelerated Anthelmintic Discovery

描述（由申请人提供）：由蠕虫（线虫和扁虫）引起的被忽视的热带病（NTDs）在极度贫困的发展中国家持续存在社会经济不稳定，造成致残性发病率和/或大量死亡率。蠕虫病的流行程度是惊人的。淋巴丝虫病是由包括马来布鲁氏菌在内的线虫引起的，在81个疾病流行国家中，全世界有1.2亿多人受到影响，有12亿多人面临风险。血吸虫是血吸虫病的病原，是致病性最强的扁形虫，感染人数超过2亿人，有超过6.5亿人面临感染风险。在可预见的未来，非传染性疾病控制工作的关键仍然是使用驱虫药——但令人担忧的是，有效的药物很少，阻碍了这些控制策略。因此，迫切需要新的、更有效的化疗方法。使问题更加复杂的是，在没有财政激励的情况下，制药业不愿满足对非传染性疾病药物的需求。本应用程序旨在通过提出我们发现和开发治疗被忽视热带病药物的方式的范式转变来解决这一问题。我们建议在爱荷华州立大学和麦吉尔大学的学术实验室和辉瑞公司之间建立一种创新的公私合作伙伴关系。学术实验室将把时间和资源投入到潜在新药靶点的分子鉴定和验证中。辉瑞动物保健（PAH）将推进选定的有效先导靶点进行基于机制的筛选。该提议的底物的主要靶点是寄生线虫B. malayi和寄生扁形虫Schistosoma mansoni中的G蛋白偶联乙酰胆碱受体和乙酰胆碱门控氯通道。该项目的第一阶段将在学术实验室进行，并将证明作用于这些受体的药物有潜力成为新型驱虫药。这些实验将结合生物成像技术、RNA干扰（RNAi）、生物测定、生理学和药理学，以确定哪些受体将进入PAH项目的下一阶段。在这里，选定的受体将被筛选，以多环芳烃为代价，与一个庞大的化合物库相比，我们相信，其中将是对我们的受体具有活性的小分子。这些活性化合物作为抗寄生虫药物的前景将在学术实验室和PAH内部进行探索，前提是材料转让协议和化合物的可用性。这一项目的成功完成将对开发新的驱虫药物产生真正重大的影响，并有可能对全世界数亿人的健康产生积极影响。此外，我们将极大地推进我们对基本蠕虫生物学的理解，并解决我们对线虫和扁虫生理和功能的理解中的一些重要知识空白。

DESCRIPTION (provided by applicant): Neglected Tropical Diseases (NTDs) caused by helminths (nematodes and flatworms) perpetuate socioeconomic instability in profoundly impoverished developing countries, inflicting crippling morbidity and/or significant mortality. The prevalence of helminth disease is staggering. Lymphatic filariasis is caused by nematodes including Brugia malayi and afflicts over 120 million people worldwide with over 1.2 billion at risk in 81 disease endemic countries. Schistosomes, the etiological agents of schistosomiasis, are the most pathogenic flatworms, infecting over 200 million with more than 650 million at risk. The lynchpin of NTD control efforts for the foreseeable future will remain the administration of anthelmintic drugs - but worryingly few effective drugs exist, hampering these control strategies. Thus there is a pressing need for new, more effective chemotherapies. Compounding the problem is the reticence of the pharmaceutical industry to engage this need for NTD drugs without the motivation of a financial incentive. This application aims to address this problem by proposing a paradigm shift in the way we discover and develop drugs for NTDs. We propose an innovative Public-Private Partnership between academic laboratories at Iowa State University and McGill University, and Pfizer, Inc. The academic laboratories will invest their time and resources in the molecular identification and validation of potential novel drug targets. Pfizer Animal Health (PAH) will advance selected validated lead targets for mechanism-based screening. The lead targets forming the substrate of this proposal are G protein-coupled acetylcholine receptors and acetylcholine-gated chloride channels in the parasitic nematode B. malayi and the parasitic flatworm Schistosoma mansoni. The first phase of the project will take place in the academic laboratories and will show that drugs acting on these receptors have potential as novel anthelmintics. The experiments will combine bioimaging techniques, RNA interference (RNAi), bioassays, physiology and pharmacology to determine which of these receptors will progress to the next phase of the project at PAH. Here selected receptors will be screened, at PAH expense, against a vast compound library amongst which, we believe, will be small molecules with activity at our receptors. The promise of these active compounds as antiparasitic drugs will be explored both in the academic laboratories and in-house at PAH, subject to material transfers agreement and compound availability. Successful completion of this project will have a truly significant impact on the development of new anthelmintic drugs and has the potential to positively impact the health of hundreds of millions of people worldwide. Further, we will greatly advance our understanding of basic worm biology and address some important knowledge gaps in our understanding of nematode and flatworm physiology and function. PUBLIC HEALTH RELEVANCE: This project forms an innovative Public-Private Partnership to accelerate the discovery of new compounds to treat devastating parasitic worm infections. Academic laboratories will identify and describe potential drug targets in the worms, and Pfizer Animal Health will screen vast libraries of compounds across these targets.