The Daniel K. Inouye College of Pharmacy
University of Hawaii at Hilo
Natural Product Drug Discovery for Emerging Parasitic Nematode Disease
Neuroangiostrongyliasis, or rat lungworm disease, is an emerging tropical disease caused by a parasitic roundworm, Angiostrongylus cantonensis. Humans become infected following ingestion of snails or slugs harboring the infectious third-stage L3 larvae, which then invade the brain and spinal cord, resulting in a constellation of neurological symptoms and signs, occasionally leading to coma or death. Currently, there is no effective treatment for this neglected tropical disease. Natural products have served as an excellent source for anti-parasitic drug discovery. Recently, an INBRE investigator has established a unique natural product library from Hawaiian endophytic fungi and other microorganisms. The proposed collaborative project will capitalize on the complementary expertise of a natural product chemist (Dr. Shegung Cao), a malacological parasitologist (Dr. Robert H. Cowie) and a medical parasitologist (Dr. William L. Gosnell) to screen this natural product library for novel compounds with motility-inhibition bioactivity to halt the transmigration of L3 larvae. Bioactive compounds will then be purified as potential therapeutics for neuroangiostrongyliasis. The objective will be achieved by the following specific aims.
Specific Aim 1. Test the efficacy of natural product compounds on infectious A. cantonensis larvae. Approach: High-throughput screening of 2,000 fractions from a natural product library will be performed against L3 larvae using an infrared-based motility-inhibition bioassay.
Specific Aim 2. Identify and characterize motility-inhibition bioactive natural product compounds through assay-guided separation and structure elucidation.
Approach: Assay-guided separation and bioactive compound structures will be determined using high-performance liquid chromatography and nuclear magnetic resonance and mass spectrometry.
This INBRE-COBRE collaboration will strengthen the research infrastructure for natural product drug discovery and molecular medicine, two primary research themes of the INBRE program, and address the COBRE mission of reducing human suffering from emerging infectious diseases through the development of effective therapeutics. This project will also provide research experience opportunities for ethnically diverse and socioeconomically disadvantaged undergraduate students in the state of Hawaii.