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: 10090820
• 负责人: JONATHAN S MARCHANT
• 金额: $ 37.37万
• 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/10090820
• 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; Effectiveness; 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; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Platyhelminths; Population; Praziquantel; Praziquantel resistance; Preparation; Property; Research; Risk; Schistosoma; Schistosoma mansoni; Schistosomiasis; School-Age Population; Series; Site; Source; Structure; Structure-Activity Relationship; Surface; TRP channel; Testing; Time; Triage; Validation; Wisconsin; Work; analog; base; chemotherapy; clinically relevant; cohort; counterscreen; cytotoxic; cytotoxicity; follow-up; helminth infection; high throughput screening; improved; in vivo; inhibitor/antagonist; 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

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.

项目概要 世界上超过三分之一的人口感染了寄生虫。最严重的感染之一 是由寄生扁虫引起的被忽视的热带病血吸虫病（血吸虫病）的基础 血吸虫属，全世界约有 2 亿人受其影响。主要药物治疗 治疗血吸虫病和其他几种寄生虫感染的药物是吡喹酮 (PZQ)。然而， PZQ 的几个功能受到严重限制。其中包括 PZQ 无法杀死寄生菌的所有阶段 生命周期、根据 PZQ 次优治愈率和现场报告对 PZQ 作为单一疗法的临床依赖 耐药性，以及无法改进 PZQ 药效团或从机制上定义这种情况 药物起作用。因此，需要开发下一代驱虫药，最好能有效对抗 广谱 PZQ 敏感蠕虫寄生虫。 我们的实验室通过发现 PZQ 在寄生血吸虫中的靶标提供了新的重要见解 [1， 2]。我们最近在 曼氏血吸虫再现了 PZQ 对血吸虫的作用特征：纳摩尔效力， (R)-PZQ 的立体选择性，以及介导持续的细胞毒性 Ca2+ 进入 [1, 2]。有了这个目标， 现在可以进行筛选活动来识别该通道的新型配体/调节剂 作为下一代驱虫药的潜力。因此，为了巩固这一突破，我们组建了 团队结合了高通量筛选 (HTS)、先导化合物优先级和优化方面的专业知识 (Scripps 佛罗里达州），以及寄生扁虫生物学的内部专业知识（威斯康星医学院，MCW）。 该团队将 (i) 对 Sm.TRPMPZQ（佛罗里达州斯克里普斯）执行初步筛选，并 (ii) 验证结果 使用小鼠模型在体外和体内对寄生血吸虫的功效进行了验证 血吸虫病感染（MCW）。还将针对其他种类的血吸虫对优先命中进行评估 蠕虫，以及从长远来看具有临床相关性的其他寄生扁虫。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 小型化以及所提议的命中验证管道的可行性。 拟议的活动与该 FOA 相关，支持 (i) 新型小分子的鉴定 具有治疗传染病的潜力，并且 (ii) 对寄生虫 TRP 离子的生物学产生新的见解 迄今为止，这些通道作为新的药物靶点很少受到关注。如果成功的话，这些活动将 提供有潜力用作下一代抗寄生虫药的新先导化合物。