Identification of targets of the antiparasitic drug praziquantel

抗寄生虫药吡喹酮靶标的鉴定

基本信息

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
项目类别：
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

项目摘要

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.

项目概要寄生虫感染血吸虫病困扰着全世界 2 亿多人，临床上使用单一药物吡喹酮 (±PZQ) 尽管±PZQ 几十年来一直是一种强有力的驱虫药，但这种药物作用的分子基础仍未明确，缺乏机制知识阻碍了理性的研究。治疗替代方案的设计，并且面对血吸虫菌株的出现令人担忧 ±PZQ 暴露对 ±PZQ 的耐受性对于所有寄生生命周期阶段均无效。因此，需要±PZQ作用的靶标及其效应器来开发改进的驱虫疗法。该 R01 应用基于支持 PZQ 是血清素样配体这一前提的初步数据我们的实验室最近确定了 R-PZQ 和 S- 的靶标。 PZQ，±PZQ 临床制剂中的两种对映体，R-PZQ 是人 5-HT2B G 蛋白的配体。偶联受体 (5-HT2B GPCR)，S-PZQ 是人类瞬时受体的血清素调节剂这些发现很重要，因为它们 (i) 提供了可能的线索。寄生虫中 PZQ 对映体的靶标（5-HT GPCR 和 TRP 通道），并且 (ii) 证明 PZQ 确实不作为选择性抗寄生虫药，但在宿主中也具有活性，值得注意的是±PZQ 会急剧改变血管。 5-HT GPCR 长期参与成虫所在的肠系膜血管内的张力。肝星状细胞中的虫卵沉积物可抑制由炎症反应引起的纤维化变化将这种有益的宿主和有害的寄生活动结合在一起提供了一条新的途径。产生改进的抗寄生虫疗法，杀死蠕虫并防止它们造成的组织损伤。根据我们的发现，我们将绘制 R-PZQ 在 5-HT2BR 上的结合位点和 S-PZQ 在 TRPM8 上的结合位点，并使用这些结合构成了血吸虫生物胺能 GPCR 中类似结合结构的识别（目标 1）和 TRP 通道（目标 2）：根据这一策略，我们最近发现了一种血吸虫 TRP 通道。受 PZQ (10) 调节——这是在扁形虫中发现的第一个 PZQ 靶标。驱虫药的宿主生物活性（目标 3）在对脉管系统的急性影响方面的临床意义，以及对肝星状细胞的慢性影响，引发纤维化变化，从而支撑许多病理学我们的合作团队汇集了 5-HT2B 受体结构、TRP 方面的专业知识。通道生物学和血管生理学以执行从分子（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，我们的活动将得到解决。 ±PZQ 的靶标和效应器将有助于开发更好的驱虫疗法和辅助药物。