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：
10612112
负责人：
John D Chan
金额：
$ 16.58万
依托单位：
UNIVERSITY OF WISCONSIN OSHKOSH
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612112
关键词：
Development non sedative parasite selective

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：被忽视的热带疾病血吸虫病是由感染的寄生流血引起的全球> 2.3亿人。当前的治疗仅依赖于一种药物Praziquantel（PZQ）。 PZQ是对最近获得性成熟的最近获得的寄生虫无效。 PZQ也不会杀死血块直接。这些缺点，以及新兴治疗的寄生虫菌株的前景强调需要控制血吸虫病的替代疗法。长期目标是确定改善了抗固定体药物。因此，该建议将研究一组替代化合物具有良好的抗寄生活性，苯二氮卓类药物。苯二氮卓铅可有效治疗血吸虫病，但对引起镇静的人类GABAAR具有很高的亲和力。总体目标该应用是为了识别棘突苯二氮卓的衍生物Meclonazepam，该衍生物保留了抗 - 寄生活动和对引起镇静的Gabaar子类型的亲和力。中心假设是苯二氮卓类疗法随着宿主加巴人的参与度减少将使镇静和保留斑点活性。该项目的理由是，尽管主机镇静是由毒品行动驱动的 α1gabaar，血吸虫基因组完全缺乏Gabaars。因此，加巴尔无法解决苯二氮卓类药物的寄生作用。相反，初步数据表明meclonazepam作用于寄生虫 CA2+通道。由于该药物的“靶标”寄生虫受体和“脱靶”宿主受体不同，因此应该有可能以提高的选择性开发治疗方法。这将通过追求两个特定的目的：1）开发麦伦西ep的类似物，在哺乳动物α1gabaars上具有改善的活性。 2）块通过与α1Gabaar拮抗剂的麦克洛西匹马混合在体内镇静。在第一个目标下，我们将合成Meclonazepam类似物，并在结合中筛选这些和其他亚型选择性苯二氮卓类药物针对哺乳动物Gabaars的测定法。然后将筛选具有改进的Gabaar亲和力的化合物反对识别寄生虫选择衍生物的血块。最后，将斑点配体筛选血吸虫病的鼠模型，以评估相对于麦伦辛ep的效率基准。在第二个目的，我们将评估Meclonazepam的体内镇静作用（以及AIM 1中的命中）和盖子 α1gabaar选择性拮抗剂的镇静作用。 Rotarod测试将用于确定镇静剂量每种化合物，然后将其与拮抗剂的比例不同，以确定混合物的混合物清除具有最小副作用的寄生虫。提出的研究很重要因为它将推进新的棘突铅 - 没有药物治疗血吸虫病的药物已获得FDA批准自1982年以来。这项研究具有创新性，将Chan博士的寄生虫学专家与医学结合在一起 Cook博士的化学专家，Gabaar亚型的基本物业和药理学专家。