Identification of targets of the antiparasitic drug praziquantel

抗寄生虫药吡喹酮靶标的鉴定

• 批准号: 10592263
• 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/10592263
• 关键词: Acute; 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; 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; 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; pharmacologic; 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在全球范围内遭受超过2亿人的痛苦，并在临床上使用 一种药物，praziquantel（±pzq）。尽管±PZQ一直是坚强的驱虫，但数十年 该药物作用的分子基础仍然不确定。缺乏机械知识阻碍了理性的 替代疗法的设计，面对呈现的黑素菌株的出现，令人担忧 给定±PZQ对±PZQ暴露的耐火性与所有寄生生命周期阶段无效。深入了解 因此，需要±PZQ作用的靶标及其作用，以发展改善的驱虫疗法。 该R01应用程序基于初步数据，该数据支持PZQ是一种类似5-羟色胺的配体 在寄生虫和人类宿主中。我们的实验室最近确定了R-PZQ和S-的目标 PZQ，±PZQ的临床公式中的两个对映异构体。 R-PZQ是人类5-HT2B G蛋白的配体 耦合受体（5-HT2B GPCR），S-PZQ是人类瞬态受体的血清素能调节剂 潜在的Melastatin 8离子通道（TRPM8）。这些发现很重要，因为它们（i）为可能的可能 寄生虫（5-HT GPCR和TRP通道）中的PZQ对映异构体的靶标，（ii）证明PZQ确实 不充当选择性的反寄生虫，而是在宿主中活跃。值得注意的是±PZQ急性改变血管 成年蠕虫居住的肠系膜血管中的音调。 5-HT GPCR的长期参与 在肝脏星状细胞中，抑制了沉积在沉积在的蠕虫卵中引起的纤维化变化 宿主组织。融合这种有益的宿主和有害的寄生活动为通往 产生改善的抗寄生虫疗法，可杀死蠕虫并防止其造成的组织损害。 根据我们的发现，我们将在5-HT2BR上绘制R-PZQ的绑定位点，在TRPM8上绘制S-PZQ并使用 这些结合位置，以识别血吸虫生物胺能GPCR中类似结构的结构（AIM 1）和 TRP通道（AIM 2）。遵循此策略，我们最近确定了一个螺旋体TRP通道 由PZQ（10）调节 - 在扁虫中鉴定出的PZQ的第一个目标。最后，我们将解决 驱虫药的宿主生物活性的临床意义（AIM 3）在急性对脉管系统的影响方面和 慢性影响启动纤维化变化的肝星状细胞，这是许多病理的基础 慢性血吸虫病。我们的合作团队将5-HT2B受体结构的专业知识汇集在一起​​，TRP 通道生物学和血管生理学从分子（受体结构）到体内执行活性 病理（调节寄生虫感染和肝病的机制）。如果成功，我们的活动将解决 ±PZQ的靶标和效果将能够发展出更好的驱虫疗法和辅助功能。