Identification of targets of the antiparasitic drug praziquantel

抗寄生虫药吡喹酮靶标的鉴定

• 批准号: 10370365
• 负责人: JONATHAN S MARCHANT
• 金额: $ 44.45万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370365
• 关键词: Acute; Address; Adult; Agonist; Anemia; Anthelmintics; Antiparasitic Agents; Architecture; Beds; Binding; Binding Sites; Biology; Bladder; Blood Vessels; Chronic; Clinical; Coupled; Data; Deposition; Development; Disease; Drug Interactions; Exhibits; Fibrosis; Formulation; G-Protein-Coupled Receptors; Granuloma; Growth; HIV Infections; Helminths; Hepatic; Hepatic Stellate Cell; Human; Hypertension; Immune response; In Vitro; Infection; Inflammatory; Intestines; Ion Channel; Knowledge; Laboratories; Left; Length; Life Cycle Stages; Ligands; Liver; Liver diseases; Malnutrition; Maps; Mesentery; Molecular; Outcome; Parasites; Parasitic Diseases; Parasitic infection; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Physiology; Platyhelminths; Population; Praziquantel; Praziquantel resistance; Property; Publishing; Reaction; Refractory; Resolution; Risk; Route; Schistosoma; Schistosomatidae; Schistosomiasis; Serotonin; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; Structure; TRP channel; Tetrahydroisoquinolines; Therapeutic; Tissues; Urogenital Diseases; Variant; Work; base; burden of illness; clinical efficacy; clinically significant; comorbidity; design; disability-adjusted life years; drug action; drug development; egg; enantiomer; gastrointestinal; improved; in vivo; insight; neglected tropical diseases; next generation; novel; prevent; rational design; receptor; screening; spastic paralysis

PROJECT SUMMARY The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated using a single drug, praziquantel (±PZQ). Although ±PZQ has served as a stalwart anthelmintic for decades, the molecular basis of action of this drug remains undefined. This lack of mechanistic knowledge impedes rational design of alternative therapeutics and is worrisome in the face of emergence of schistosome strains exhibiting refractoriness to ±PZQ exposure given ±PZQ is ineffective against all parasitic life cycle stages. Insight into the targets of ±PZQ action, and their effectors, is therefore needed to develop improved anthelmintic therapies. This R01 application is based around preliminary data supporting a premise that PZQ is a serotonin-like ligand in both the parasite and the human host. Our laboratory has recently identified targets for both R-PZQ and S- PZQ, the two enantiomers in the clinical formulation of ±PZQ. R-PZQ is a ligand at the human 5-HT2B G protein coupled receptor (5-HT2B GPCR), and S-PZQ is a serotonergic regulator of the human transient receptor potential melastatin 8 ion channel (TRPM8). These findings are significant as they (i) provide clues to the likely targets of PZQ enantiomers in the parasite (5-HT GPCRs & TRP channels) and (ii) demonstrate that PZQ does not act as a selective antiparasitic, but also is active in the host. Notably ±PZQ acutely changes blood vessel tone within the mesenteric blood vessels where the adult worms reside. Chronic engagement of 5-HT GPCRs in hepatic stellate cells inhibited fibrotic changes caused by inflammatory reactions to worm eggs deposited in host tissues. Coalescing such beneficial host and deleterious parasitic activities provides a novel route to generating improved antiparasitic therapies that kill worms and prevent the tissue damage they cause. Based on our discoveries, we will map the binding sites of R-PZQ on 5-HT2BR, and S-PZQ on TRPM8 and use these binding poses to identify similar binding architectures in schistosome bioaminergic GPCRs (Aim 1) and TRP channels (Aim 2). Following this strategy, we have recently identified a schistosome TRP channel that is regulated by PZQ (10) – the first target of PZQ ever identified in a flatworm. Finally, we will address the clinical significance of host bioactivity of anthelmintics (Aim 3) in terms of acute effects on the vasculature, and chronic effects on hepatic stellate cells that initiate fibrogenic changes underpinning many of the pathologies of chronic schistosomiasis. Our collaborative team bring together expertise in 5-HT2B receptor structure, TRP channel biology and blood vessel physiology to execute activities from molecular (receptor structure) to in vivo pathology (mechanisms regulating parasite infection and liver disease). If successful, our activities will resolve targets and effectors for ±PZQ that will enable development of better anthelmintic therapies and adjuncts.

项目摘要 寄生虫感染血吸虫病折磨着全世界超过2亿人， 单药吡喹酮（±PZQ）。尽管±PZQ几十年来一直是一种坚定的驱虫剂， 这种药物作用的分子基础仍不清楚。这种机械知识的缺乏阻碍了理性 替代疗法的设计，并且在面对表现出抗病毒性的病毒株的出现时令人担忧， 给定±PZQ的± PZQ暴露的不应性对所有寄生生命周期阶段无效。洞察 因此，需要±PZQ作用的靶点及其效应物来开发改进的驱虫疗法。 该R 01应用基于支持PZQ是一种类胡萝卜素配体的前提的初步数据 在寄生虫和人类宿主体内。我们的实验室最近已经确定了R-PZQ和S- PZQ，±PZQ临床制剂中的两种对映体。R-PZQ是人5-HT 2B G蛋白的配体 偶联受体（5-HT 2B GPCR），S-PZQ是人瞬时受体的多巴胺能调节剂 潜在的melastatin 8离子通道（TRPM 8）。这些发现是重要的，因为它们（i）提供线索， PZQ对映体在寄生虫中的靶点（5-HT GPCR和TRP通道）和（ii）证明PZQ确实 不作为选择性抗寄生虫药，但在宿主中也有活性。显著±PZQ急性改变血管 蠕虫所在的肠系膜血管内的张力。5-HT GPCR的慢性参与 抑制肝星状细胞中的纤维化变化所引起的炎症反应，以蠕虫卵沉积在 宿主组织结合这种有益的宿主和有害的寄生活动提供了一种新的途径， 产生了改进的抗寄生虫疗法，可以杀死蠕虫并防止它们引起的组织损伤。 基于我们的发现，我们将绘制R-PZQ在5-HT 2BR上的结合位点和S-PZQ在TRPM 8上的结合位点，并使用 这些结合位姿用于鉴定双链体生物胺能GPCR中的类似结合结构（Aim 1）， TRP通道（目标2）。根据这一策略，我们最近发现了一个麻烦的TRP通道， 受PZQ调节（10）-在扁形虫中发现的第一个PZQ靶点。最后，我们将讨论 驱虫剂的宿主生物活性的临床意义（目的3）在对血管系统的急性影响方面，以及 对肝星状细胞的慢性作用引发纤维化变化，支持许多肝硬化的病理学。 慢性血吸虫病我们的合作团队汇集了5-HT 2B受体结构、TRP 通道生物学和血管生理学执行从分子（受体结构）到体内的活动 病理学（调节寄生虫感染和肝脏疾病的机制）。如果成功，我们的行动将解决 ±PZQ的靶点和效应物，这将有助于开发更好的驱虫疗法和药物。