Cholinergic Receptors as Targets for Accelerated Anthelmintic Discovery

胆碱能受体作为加速驱虫药发现的目标

• 批准号: 8452716
• 负责人: Michael John Kimber
• 金额: $ 30.76万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452716
• 关键词: Acetylcholine; Address; Animals; Anthelmintics; Antiparasitic Agents; Biological Assay; Biology; Brugia malayi; Cell Line; Cellular biology; Chloride Channels; Cholinergic Receptors; Chronic; Classification; Co-Immunoprecipitations; Complement; Country; Coupled; Data; Developing Countries; Development; Disease; Drug Industry; Drug Targeting; Endemic Diseases; Family; Filarial Elephantiases; Future; GTP-Binding Proteins; Genome; Genomics; Goals; Health; Helminths; Housing; In Vitro; Infection; Iowa; Knowledge; Laboratories; Lead; Libraries; Ligands; Methodology; Mining; Modality; Molecular; Molecular Biology; Morbidity - disease rate; Motivation; Muscarinic Acetylcholine Receptor; Nematoda; Parasites; Parasitic nematode; Pathogenicity; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Physiological; Physiology; Platyhelminths; Prevalence; Protocols documentation; RNA Interference; Research; Research Personnel; Resources; Risk; Schistosoma; Schistosoma mansoni; Schistosomiasis; System; Techniques; Testing; Time; Tissues; Tropical Disease; Universities; Validation; Xenopus oocyte; base; bioimaging; chemotherapy; cholinergic; disorder control; drug candidate; drug development; experience; financial incentive; global health; immunocytochemistry; in vivo; innovation; interest; material transfer agreement; mortality; neglect; neuromuscular; novel; public health relevance; public-private partnership; receptor; research study; response; screening; small molecule; socioeconomics; stoichiometry; therapeutic target

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.

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（NTD）使极度贫困的发展中国家社会经济长期不稳定，造成严重的发病率和/或显着的死亡率。蠕虫病的患病率是惊人的。淋巴丝虫病是由包括马来丝虫在内的线虫引起的，全世界有超过 1.2 亿人受其困扰，其中 81 个疾病流行国家中超过 12 亿人面临风险。血吸虫是血吸虫病的病原体，是致病性最强的扁虫，感染人数超过 2 亿，其中超过 6.5 亿人处于危险之中。在可预见的未来，NTD 控制工作的关键仍然是使用驱虫药物，但令人担忧的是，有效的药物很少，这阻碍了这些控制策略。因此，迫切需要新的、更有效的化疗。使问题更加复杂的是，在没有经济激励的情况下，制药行业不愿满足对 NTD 药物的需求。该申请旨在通过提出我们发现和开发 NTD 药物方式的范式转变来解决这个问题。我们提议在爱荷华州立大学和麦吉尔大学的学术实验室与辉瑞公司之间建立创新的公私合作伙伴关系。学术实验室将投入时间和资源来对潜在的新药物靶点进行分子鉴定和验证。辉瑞动物保健公司（PAH）将推进选定的经过验证的主要目标，以进行基于机制的筛查。构成该提案底物的主要靶标是寄生性马来线虫和寄生扁虫曼氏血吸虫中的 G 蛋白偶联乙酰胆碱受体和乙酰胆碱门控氯离子通道。 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具有作为新型驱虫药的潜力。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，选定的受体将以 PAH 为代价，针对一个巨大的化合物库进行筛选，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，具体取决于材料转让协议和化合物的可用性。该项目的成功完成将对新型驱虫药物的开发产生真正重大的影响，并有可能对全球数亿人的健康产生积极影响。此外，我们将极大地增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学和功能的理解中的一些重要知识空白。