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

项目摘要/摘要 夏威夷在报告的人类血管圆线虫病或老鼠肺虫病(RLW)病例方面居全国首位。 由寄生线虫血管线虫引起的潜在致死性中枢神经系统感染 广州。没有专门针对广州管圆线虫的驱虫药。因此，迫切需要 存在着为这种新出现的和被忽视的热带疾病开发有效的药物。天然产品是 治疗寄生虫病的最佳药物来源，就像以前证明的寄生虫病，如 作为治疗疟疾的青蒿素，治疗河盲症和淋巴丝虫病的伊维菌素。我们的长期目标是 从包括未被开发的夏威夷真菌在内的微生物中鉴定新的驱虫天然产品 和细菌。这项拟议的研究的目标是发现能够使 感染第三期广州管圆线虫幼虫(L3)。我们的中心假设是天然产品，如 夏威夷未被开发的内生真菌和其他微生物是抗A. 广州天然产物药物发现。这项拟议研究的理由是，曾经是新奇的 确定了有效的抗RLW天然产物，将研究先导化合物的作用机理 行动，并在不久的将来在体内测试。这个项目的目标将通过两个方面来实现 具体目标：(1)筛选抗传染性广州管圆线虫L3的NPs；(2)鉴定和表征运动性 通过分析指导分离和结构鉴定来抑制和降低生物活性NPs的活性；以及 评估血脑屏障(BBB)的通透性和疗效。这项研究具有创新性，因为它(A)使用： 我们新建立的高通量筛查(HTS)分析，以筛选我们新的和独特的天然 产品文库(NPL)；和(B)利用一种新的基于红外线的运动抑制生物测定来 从我们的NPL中筛选出抗感染性L3幼虫的组分。拟议的项目意义重大，因为它 旨在通过开发有效的新发传染病来减少人类的痛苦 治疗，并将加强天然产物药物发现和研究基础设施 夏威夷的分子医学。我们的方法可以作为实施天然产物药物的典范 针对其他新出现的寄生虫病的发现。该项目还将提供研究 为研究生以及不同种族和社会经济背景的人提供经验机会 夏威夷的弱势本科生。

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.