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 世界上超过三分之一的人口感染了寄生蠕虫。最严重的感染之一 这是一种被忽视的热带疾病血吸虫病（Bilharzia）的基础， 血吸虫属，它折磨着全世界约2亿人。主要的药物治疗 治疗血吸虫病和其他几种寄生蠕虫感染的药物是吡喹酮（PZQ）。然而，在这方面， PZQ的几个特征受到严重限制。这些包括PZQ无法杀死寄生虫的所有阶段 生命周期，根据PZQ的次优治愈率和现场报告，临床依赖PZQ作为单药治疗 耐药性，以及无法改善PZQ药效团或机械地定义这是如何发生的。 药物有效。因此，需要开发下一代驱虫剂，理想地是对寄生虫有活性的。 广谱PZQ敏感蠕虫寄生虫。 我们的实验室通过在寄生虫体中发现PZQ的靶点提供了新的关键见解[1， 2]。最近，我们发现了一个钙渗透性瞬时受体电位（TRP）离子通道（Sm.TRPMPZQ）， 曼氏血吸虫，再现了PZQ对染色体作用的特征：纳摩尔效力， （R）-PZQ的立体选择性和介导持续的细胞毒性Ca 2+进入[1，2]。有了这个目标， 现在有可能进行筛选活动以鉴定该通道的新配体/调节剂， 作为下一代驱虫药的潜力。因此，为了实现这一突破，我们召集了一个 团队结合了高通量筛选（HTS）、先导物优先级和优化方面的专业知识（Scripps 佛罗里达），以及寄生扁形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佛罗里达）进行初步筛选，并（ii）验证结果 体外和体内使用小鼠模型， 血吸虫病感染（MCW）。优先命中也将评估对其他物种的寄生虫 蠕虫，并在长期的其他寄生扁形虫与临床相关。试点筛选和验证 作为初步数据提供的数据支持靶标鉴定、测定优化和 小型化和所提出的用于命中验证的流水线的可行性。 拟定活动与本FOA相关，支持（i）鉴定新型小分子 具有治疗传染病的潜力，以及（ii）对寄生虫TRP离子生物学产生新的见解 通道，迄今为止作为新的药物靶点很少受到关注。如果成功，这些活动将 提供具有用作下一代抗寄生虫药潜力的新引线。