Antiparasitic Agent Discovery from Natural Products for the Treatment of a Globally Emerging Disease

项目总结/摘要 夏威夷报告的人类管圆线虫病或鼠肺线虫病（RLW）病例居全国首位， 由寄生线虫管圆线虫引起的潜在致命的中枢神经系统感染 广东话。专门针对A.广州没有。因此，迫切需要 目前正在为这种新出现的被忽视的热带疾病开发有效的药物。天然产品是 寄生虫病的最佳药物线索来源，如以前证明的寄生虫病， 如治疗疟疾的青蒿素、治疗河盲症和淋巴丝虫病的伊维菌素。我们的长期目标是 从微生物中鉴定新驱虫剂天然产物 和细菌。拟议研究的目的是发现天然产品， 感染性第三阶段A.广州蚜幼虫（L3）。我们的中心假设是， 在夏威夷未被开发的内生真菌和其它微生物是抗A的丰富来源。 广东天然产物药物发现。这项研究的基本原理是， 有效的抗RLW天然产物被确定，先导化合物将被研究其机制， 并在不久的将来进行体内测试。该项目的目标将通过两个 具体目的：（1）筛选抗感染性A.（2）鉴定和表征运动性 通过测定引导的分离和结构解析抑制和降低生物活性NP的活力，以及 评估血脑屏障（BBB）渗透性和功效。这项研究是创新的，因为它：（a）使用 我们新建立的高通量筛选（HTS）试验，以筛选我们新的和独特的天然 产物库（NPL）;和（B）利用新的基于红外的运动抑制生物测定， 筛选来自我们的NPL的组分对抗感染性L3幼虫。该项目之所以重要，是因为它 旨在通过发展有效的 治疗学，并将加强天然产物药物发现的研究基础设施， 在夏威夷的分子医学我们的方法可以作为一个模式，开展天然产物药物 新发现的寄生虫病。该项目还将提供研究 体验研究生和种族多样性和社会经济的机会 夏威夷州的贫困大学生。

PROJECT SUMMARY/ABSTRACT Hawaii leads the nation in reported cases of human angiostrongyliasis, or rat lungworm (RLW) disease, a potentially lethal central nervous system infection caused by the parasitic nematode Angiostrongylus cantonensis. Anthelmintics specifically targeting A. cantonensis are not available. Thus, an urgent need exists to develop effective drugs for this emerging and neglected tropical disease. Natural products are the best source of drug leads for parasitic diseases, as previously demonstrated for parasitic diseases, such as artemisinin for malaria, Ivermectin for river blindness and lymphatic filariasis. Our long-term goal is to identify novel anthelmintic natural products from microorganisms including under-explored Hawaiian fungi and bacteria. The objective of the proposed research is to discover natural products that immobilize infectious third stage A. cantonensis larvae (L3). Our central hypothesis is that natural products such as the under-explored endophytic fungi in Hawaii and other microorganisms are a rich source for anti-A. cantonensis natural product drug discovery. The rationale of the proposed research is that once novel potent anti-RLW natural products are identified, lead compounds will be studied for their mechanisms of action and tested in vivo in the near future. The objectives of this project will be accomplished by two specific aims: (1) Screen NPs against infectious A. cantonensis L3; (2) Identify and characterize motility inhibiting and viability reducing bioactive NPs via assay-guided separation and structure elucidation, and assess Blood-brain barrier (BBB) permeability and efficacy. This study is innovative because it: (a) uses our newly established high-throughput screening (HTS) assay to screen our new and unique natural product library (NPL) against RLW; and (b) utilizes a new infrared-based motility-inhibition bioassay to screen fractions from our NPL against infectious L3 larvae. The proposed project is significant because it aims to reduce human suffering from emerging infectious diseases through the development of effective therapeutics, and will strengthen the research infrastructure for natural product drug discovery and molecular medicine in Hawaii. Our approach could serve as a model for carrying out natural product drug discovery against other newly emerging parasitic diseases. This project will also provide research experience opportunities for graduate students and ethnically diverse and socioeconomically disadvantaged undergraduate students in the state of Hawaii.