Identification of novel anthelmintics through a target-based screen of a parasite ion channel

通过基于目标的寄生虫离子通道筛选鉴定新型驱虫药

• 批准号: 10561687
• 负责人: JONATHAN S MARCHANT
• 金额: $ 69.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561687
• 关键词: Adult; Affinity; Anthelmintics; Antiparasitic Agents; Attention; Biological Assay; Biology; Characteristics; Child; Clinic; Clinical; Collaborations; Communicable Diseases; Country; Coupled; Data; Data Set; Disease; Drug Design; Drug Targeting; Electrophysiology (science); Evaluation; Exhibits; Failure; Field Reports; Florida; Generations; Goals; Hand; Health; Helminths; In Vitro; Infection; Ion Channel; Knowledge; Laboratories; Lead; Life Cycle Stages; Ligands; Light; Mediation; Miniaturization; Modeling; Molecular; Paralysed; Parasites; Parasitic Diseases; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Platyhelminths; Population; Populations at Risk; Praziquantel; Praziquantel resistance; Preparation; Property; Research; Schistosoma; Schistosoma mansoni; Schistosomiasis; School-Age Population; Series; Site; Source; Structure-Activity Relationship; Surface; TRP channel; Testing; Time; Triage; Validation; Wisconsin; Work; analog; chemotherapy; clinically relevant; cohort; counterscreen; cytotoxic; cytotoxicity; follow-up; helminth infection; high throughput screening; improved; in vivo; inhibitor; insight; lead optimization; lead series; medical schools; mouse model; nanomolar; neglected tropical diseases; new therapeutic target; next generation; novel; pharmacophore; prophylactic; receptor; response; scaffold; screening; small molecule; therapeutic effectiveness

PROJECT SUMMARY Over a third of the world's population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. The mainstay pharmacotherapy for schistosomiasis, and several other parasitic helminth infections, is the drug praziquantel (PZQ). However, several features of PZQ are severely limiting. These include an inability of PZQ to kill all stages of the parasitic life cycle, clinical reliance on PZQ as a monotherapy in light of sub-optimal cure rates and field reports of PZQ resistance, as well as an inability to improve upon the PZQ pharmacophore or define mechanistically how this drug works. Consequently, there is a need to develop next generation anthelmintics, ideally active against a broad spectrum of PZQ-sensitive helminth parasites. Our laboratory has provided new critical insight by discovering the target of PZQ in parasitic schistosomes [1, 2]. We recently identified a Ca2+-permeable transient receptor potential (TRP) ion channel (Sm.TRPMPZQ) in Schistosoma mansoni that reproduces the characteristics of PZQ action on schistosomes: nanomolar potency, stereoselectivity for (R)-PZQ, and mediation of a sustained, cytotoxic Ca2+ entry [1, 2]. With this target in hand, it is now possible to conduct a screening campaign to identify novel ligands/regulators of this channel with potential as next generation anthelmintics. Therefore, to build upon this breakthrough, we have assembled a team combining expertise in high throughput screening (HTS), lead prioritization and optimization (Scripps Florida), together with in-house expertise in parasitic flatworm biology (Medical College of Wisconsin, MCW). This team will (i) execute a primary screen against Sm.TRPMPZQ (Scripps Florida) and (ii) validate the resulting hits for efficacy against parasitic schistosome worms ex vivo, and in vivo using a murine model of schistosomiasis infection (MCW). Prioritized hits will also be evaluated against other species of schistosome worms, and in the longer term other parasitic flatworms with clinical relevance. A pilot screen and validation data presented as preliminary data support the rigor of target identification, assay optimization and miniaturization, and feasibility of the proposed pipeline for hit validation. The proposed activities have relevance to this FOA by supporting (i) the identification of novel small molecules with potential to treat infectious diseases and (ii) generation of new insight into the biology of parasite TRP ion channels, which have received little attention to date as novel drug targets. If successful, these activities will provide new leads with potential for usage as next generation antiparasitics.

项目摘要 世界三分之一以上人口感染了寄生虫。最繁重的感染之一 基础是由寄生虫引起的被忽视的热带疾病血吸虫病（比尔哈兹） 属Scistosoma属，全世界遭受了约2亿人的折磨。主要的药物治疗 血吸虫病和其他几种寄生虫的蠕虫感染是药物普拉齐特尔（PZQ）。然而， PZQ的几个功能严重限制。这些包括无法杀死寄生的所有阶段的PZQ 生命周期，依靠PZQ作为单一疗法的临床依赖，鉴于PZQ的次优率和现场报告 耐药性，以及无法改善PZQ药效团或从机械上定义如何 毒品作品。因此，有必要发展下一代的驱虫药，理想的活动是 PZQ敏感的蠕虫寄生虫的广泛谱。 我们的实验室通过发现PZQ在寄生虫中的靶标提供了新的关键见解[1， 2]。我们最近确定了Ca2+可渗透的瞬态受体电位（TRP）离子通道（SM.TRPMPZQ） 曼氏菌的血吸虫可再现PZQ对血吸虫作用的特征：纳摩尔效力， （R）-PZQ的立体选择性以及持续的，细胞毒性CA2+进入的介导[1，2]。有了这个目标， 现在可以进行筛选运动，以确定此渠道的新颖配体/调节器 作为下一代驱虫药的潜力。因此，为了建立这一突破，我们组装了一个 团队合并高吞吐量筛查（HTS），铅优先和优化方面的专业知识（Scripps 佛罗里达州），以及寄生虫生物学的内部专业知识（威斯康星州医学院，MCW）。 该团队将（i）对SM.TRPMPZQ（Scripps Florida）执行主屏幕，（ii）验证结果 对寄生虫蠕虫的疗效的命中率在体内以及使用鼠模型的体内 血吸虫病感染（MCW）。还将针对其他种类的细胞体评估优先的命中 蠕虫，从长远来看，其他具有临床相关性的寄生虫。试点屏幕和验证 作为初步数据提供的数据支持目标识别，测定优化和 小型化和提议管道的可行性用于命中验证。 提出的活动通过支持（i）识别新型小分子与该FOA相关 具有治疗传染病的潜力，以及（ii）对寄生虫生物学生物学的新见解 作为新的药物靶标，频道很少关注。如果成功，这些活动将 提供新的潜在客户，并可能作为下一代反寄生虫。