Identification of molecular target (s) of action of the anthelmintic praziquantel in the human host

驱虫吡喹酮在人类宿主中作用的分子靶标的鉴定

• 批准号: 10207383
• 负责人: Nawal Adam Yahya
• 金额: $ 4.46万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-19 至 2022-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207383
• 关键词: Adolescent; Adult; Agonist; Anthelmintics; Antiparasitic Agents; Binding; Binding Sites; Blood Vessels; Blood flow; Calcium; Chronic; Clinical; Communicable Diseases; Contracts; Country; Data; Deposition; Destinations; Developing Countries; Development; Effectiveness; Exhibits; Female; Flushing; G-Protein-Coupled Receptors; Goals; Healthcare; Heart; Helminths; Hepatic; Human; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Invaded; Ion Channel; Knowledge; Ligands; Liver; Lung; Measures; Mediating; Mesenteric Arteries; Mesentery; Mission; Modeling; Molecular Target; Mus; Myography; National Institute of Allergy and Infectious Disease; Paralysed; Parasites; Parasitic Diseases; Parasitic infection; Partner in relationship; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Platyhelminths; Praziquantel; Praziquantel resistance; Reaction; Refractory; Research; Rest; Schistosoma; Schistosoma mansoni; Schistosomatidae; Schistosomiasis; Serotonin; Serotonin Antagonists; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; TRP channel; TRPA channel; Testing; Therapeutic; Tissues; Training; Vasodilation; Work; base; burden of illness; clinical efficacy; design; egg; enantiomer; genetic manipulation; in vivo; insight; knock-down; male; mouse model; mutant; neglected tropical diseases; next generation; novel; novel therapeutics; pharmacophore; prevent; receptor; resistant strain; serotonin receptor; targeted treatment; therapeutic effectiveness; vasoconstriction; welfare

PROJECT SUMMARY The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated by a single drug, praziquantel (PZQ). Although PZQ has served as an effective clinical agent for almost four decades, several features of PZQ are less than ideal including a lack of understanding about the molecular target(s) of this drug. This lack of mechanistic information impedes rational design of alternative therapeutics and is alarming in the face of an inability of PZQ to kill all stages of the parasitic lifecycle, and the emergence of schistosome strains exhibiting refractoriness to PZQ exposure. The long-term goal of this project is to define the target(s) engaged by PZQ in vivo to facilitate development of the next-generation of anthelmintic drugs. This proposal is based upon recent observations that PZQ has been shown to interact with serotonin (5-HT) receptors in the human host. This is an interesting observation as 5-HT signaling regulates contraction of the blood vessels in which the adult blood flukes reside within the mesenteric vasculature. Whether these host vascular interactions contribute to the efficacy of PZQ as a clinical agent, and whether these interactions provide clues to the parasitic target(s) of PZQ are unanswered questions. My graduate training proposal will first focus on defining targets of PZQ in the human host. I will test the hypothesis that PZQ acts as a tryptaminergic pharmacophore in the host, interacting with tryptaminergic binding sites on specific 5-HT G protein coupled receptors (R-PZQ), and transient receptor potential channels (S-PZQ). Having identified the relevant host targets of PZQ (Aim 1), I can then assess whether PZQ interaction with these defined host signaling pathways contributes to the therapeutic effectiveness of this drug (Aim 2). A longer term significance of these activities will be for revealing likely parasitic target(s) of PZQ. Two Aims are proposed. In Aim 1, host targets of PZQ enantiomers in the host mesenteric vasculature will be defined using pharmacological and genetic manipulations in conjunction with wire myography to measure the contractile tone of isolated mesenteric arteries. In Aim 2, the importance of PZQ interactivity with the identified host receptors will be assessed in schistosome-infected mice under conditions where PZQ interactivity with host targets is impaired. Effects on mesenteric blood flow (important for flushing worms to the liver), worm and egg burden, and inflammatory damage in the mouse model of schistosomiasis will be examined. This research is significant, as it will reveal target(s) and pathways engaged by this important therapeutic that have proved unresolved over almost 40 years of clinical use. Successful completion of my project will aid identification of PZQ target(s) and thereby the development of the next generation of antischistosomal drugs.

项目摘要 寄生虫感染血吸虫病在全球范围内遭受了2亿多人的困扰，并在临床上受到 单一药物，praziquantel（PZQ）。尽管PZQ一直是有效的临床药物已有近四十年了，但 PZQ的几个特征并不理想，包括缺乏对分子靶标的理解 这种药物。缺乏机械信息阻碍了替代治疗的合理设计，并且令人震惊 面对PZQ无法杀死寄生生命周期的所有阶段，而棘手的出现 表现出对PZQ暴露的耐受性的菌株。该项目的长期目标是定义目标 由PZQ在体内参与，以促进下一代驱虫药的发展。该提议是 基于最近的观察结果，该观察已证明PZQ与5-羟色胺（5-HT）受体相互作用 人类主持人。这是一个有趣的观察结果，因为5-HT信号传导调节血管收缩 成年血液中存在于肠系膜脉管系统中。这些宿主的血管相互作用是否 有助于PZQ作为临床药物的功效，以及这些相互作用是否为寄生虫提供了线索 PZQ的目标是未解决的问题。 我的研究生培训建议将首先关注定义人类宿主中PZQ的目标。我将测试 假设PZQ充当宿主中的色氨酸能药片，并与色氨酸能结合相互作用 特定5-HT G蛋白偶联受体（R-PZQ）和瞬态受体电势通道（S-PZQ）上的位点。 确定了PZQ的相关主机目标（AIM 1），我可以评估PZQ是否与这些相互作用 定义的宿主信号通路有助于该药物的治疗有效性（AIM 2）。长期 这些活动的重要性将是揭示PZQ的可能寄生靶标。提出了两个目标。 在AIM 1中，将使用宿主肠系膜脉管系统中的PZQ映体的宿主靶标的定义 药理和遗传操作与电线密码结合以测量收缩 孤立的肠系膜动脉的音调。在AIM 2中，PZQ与已确定的主机的相互作用的重要性 在PZQ与宿主相互作用的情况下 目标受损。对肠系膜血流的影响（对于肝冲洗蠕虫很重要），蠕虫和鸡蛋 将检查小鼠血吸虫病模型中的负担和炎症损伤。这项研究是 重要的是，这将揭示目标的目标和途径 在近40年的临床用途中尚未解决。成功完成我的项目将有助于识别PZQ 靶标，从而发展下一代的反毒体药物。

项目成果

Mechanism of praziquantel action at a parasitic flatworm ion channel.

• DOI: 10.1126/scitranslmed.abj5832
• 发表时间: 2021-12-22
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Park SK;Friedrich L;Yahya NA;Rohr CM;Chulkov EG;Maillard D;Rippmann F;Spangenberg T;Marchant JS
• 通讯作者: Marchant JS