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

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.