Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis

开发非镇静、寄生虫选择性苯二氮卓类药物来治疗被忽视的热带疾病血吸虫病

基本信息

批准号：
9977580
负责人：
John D Chan
金额：
$ 4.89万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2020-04-01 至 2020-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977580
关键词：
Admixture Affinity Alternative Therapies Anthelmintics Antiparasitic Agents Attenuated Benchmarking Benzodiazepines Binding Biological Assay Cryoelectron Microscopy Data Development Diarrhea Diazepam Disease Dose Dose-Limiting Drowsiness Drug Combinations Drug Receptors Engineering Event FDA approved Genome Genomics Goals Helminths Human Impairment In Vitro Infection Intestines Lead Life Cycle Stages Ligand Binding Ligands Modeling Modernization Modification Mus Muscle Cramp Parasite resistance Parasites Parasitology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Praziquantel Praziquantel resistance Property Public Health Research Rotarod Performance Test Schistosoma Schistosomatidae Schistosomiasis Sedation procedure Structure Therapeutic Therapeutic Index Treatment Failure Vomiting analog base clinical development cooking drug action druggable target experimental study improved in vivo innovation mouse model neglected tropical diseases novel therapeutics prevent programs radioligand receptor sedative side effect urinary voltage

项目摘要

ABSTRACT: The neglected tropical disease schistosomiasis is caused by parasitic blood flukes that infect >230 million people worldwide. Current treatment is reliant on just one drug, praziquantel (PZQ). PZQ is ineffective against recently acquired parasites that have not reached sexual maturity. PZQ also does not kill schistosomes directly. These drawbacks, and the prospect of emerging treatment-resistant parasite strains, highlight the need for alternative therapies to control schistosomiasis. The long-term goal is to identify improved anti-schistosomal drugs. Therefore, this proposal will investigate an alternative group of compounds with proven anti-parasitic activity, benzodiazepines. Benzodiazepine leads are effective at treating schistosomiasis but have high affinity for the human GABAARs that cause sedation. The overall objective of this application is to identify derivatives of a schistocidal benzodiazepine, meclonazepam, that retain anti- parasitic activity and lack affinity for sedation-causing GABAAR sub-types. The central hypothesis is that that benzodiazepine therapies with decreased engagement of host GABAARs will minimize sedation and retain schistocidal activity. The rationale for this project is that while host sedation is driven by drug action at the α1GABAAR, schistosome genomes lack GABAARs entirely. Therefore, GABAARs cannot account for the anti- parasitic effects of benzodiazepines. Instead, preliminary data indicates that meclonazepam acts on parasite Ca2+ channels. Since the ‘on-target’ parasite receptor and ‘off-target’ host receptor for this drug are distinct, it should be possible to develop treatments with improved selectivity. This will be done by pursuing two specific aims: 1) Develop analogs of meclonazepam with decreased activity at mammalian α1GABAARs. 2) Block sedation in vivo by admixture of meclonazepam with α1GABAAR antagonists. Under the first aim, we will synthesize meclonazepam analogs and screen these and other sub-type selective benzodiazepines in binding assays against mammalian GABAARs. Compounds with decreased GABAAR affinity will then be screened against schistosomes to identify parasite-selective derivatives. Finally, schistocidal ligands will be screened in murine model of schistosomiasis to assess efficacy benchmarked relative to meclonazepam. In the second aim, we will assess the in vivo sedative effects of meclonazepam (as well as hits from Aim 1) and the blockade of sedation by α1GABAAR-selective antagonists. The rotarod test will be used to determine the sedating dose of each compound, which will then be administered in mixture with varying ratios of antagonists to determine an admixture that admixture clears parasites with minimized side effects. The research proposed is significant because it will advance new schistocidal leads – no drug to treat schistosomiasis has been FDA approved since 1982. This research is innovative, combining Dr. Chan’s expertise in parasitology with the medicinal chemistry expertise of Dr. Cook, an expert in fundamental properties and pharmacology of GABAAR subtypes.

摘要：被忽视的热带病血吸虫病是由感染血吸虫的寄生血吸虫引起的。目前全世界有超过 2.3 亿人仅依赖一种药物，即吡喹酮 (PZQ)。 PZQ 对新近获得的尚未达到性成熟的寄生虫无效，也不能杀死。这些问题，以及新出现的抗药性寄生虫菌株的前景，强调需要替代疗法来控制血吸虫病长期目标是确定。因此，该提案将研究一组替代化合物。苯二氮卓类药物具有已证实的抗寄生虫活性，可有效治疗。血吸虫病，但与引起镇静的人类 GABAAR 具有高亲和力。该应用旨在鉴定杀裂性苯二氮卓类药物甲氯硝西泮的衍生物，该衍生物保留了抗寄生活性并且对引起镇静的 GABAAR 亚型缺乏亲和力。中心假设是：减少宿主 GABAAR 参与的苯二氮卓类疗法将最大限度地减少镇静和保留该项目的基本原理是，宿主镇静是由药物作用驱动的。 α1GABAAR，血吸虫基因组完全缺乏 GABAAR，因此，GABAAR 不能解释抗-。相反，初步数据表明甲氯硝西泮对寄生虫起作用。由于该药物的“靶向”寄生虫受体和“脱靶”宿主受体是不同的，因此应该有可能开发出具有更高选择性的治疗方法，这将通过追求两个特定的目标来实现。目标： 1) 开发甲氯西泮类似物，降低哺乳动物 α1GABAAR 的活性 2) 阻断。通过甲氯硝西泮与 α1GABAAR 拮抗剂的混合物进行体内镇静在第一个目标下，我们将合成甲氯硝西泮类似物并筛选这些和其他亚型选择性苯二氮卓类药物的结合然后将筛选针对哺乳动物 GABAAR 亲和力降低的化合物。抗血吸虫以鉴定寄生虫选择性衍生物最后，将筛选杀血吸虫配体。第二个是用血吸虫病鼠模型来评估相对于甲氯硝西泮的疗效。目标，我们将评估甲氯硝西泮（以及目标 1 的效果）和封锁的体内镇静作用 α1GABAAR选择性拮抗剂的镇静作用旋转试验将用于确定镇静剂量。每种化合物，然后将其与不同比例的拮抗剂混合施用以确定一种混合物，可以以最小的副作用清除寄生虫。所提出的研究具有重要意义。因为它将推进新的杀血吸虫先导药物——FDA 尚未批准治疗血吸虫病的药物自 1982 年以来。这项研究具有创新性，将陈博士在寄生虫学方面的专业知识与医学知识相结合。 Cook 博士是 GABAAR 亚型的基本特性和药理学专家，其化学专业知识非常丰富。