Discovery of neuroactive natural products using behavioral assays in zebrafish

Abstract

Despite the advances of modern drug discovery, natural products-not only from plants, but also from fungi and microorganisms-remain the largest and most attractive source of chemical diversity for the development of novel therapeutics across multiple indication areas. Important technological developments within the past decade are now addressing one of the primary bottlenecks of natural product discovery-namely, the bioassay-guided isolation of pure compounds from complex natural matrices. These developments include microgram-scale analytical techniques such as UHPLC-TOF-MS and microflow NMR1. Ultimately, the utility of these new methods for natural product discovery will also depend on the biomedical relevance of the bioassays with which they are used. Towards this end, our laboratory is developing in vivo, microgram-scale, high-throughput assays based on zebrafish embryos and larvae for the systematic identification of bioactive natural products2,3. Zebrafish offer the ability to rapidly evaluate-at a very early stage in the drug discovery process-both the therapeutic potential of natural products, as well as possible hepato-, cardio-, and neurotoxicities. Due to the requirement for only microgram quantities of compounds to be tested, in vivo assays based on zebrafish are useful not only for bioassay-guided isolation, but also for the subsequence derivatization of bioactive natural products prioritized for further development as drug discovery leads. This lecture will highlight our laboratory's recent work in the isolation of neuroactive natural products using behavioral assays in zebrafish larvae, particularly in the area of epilepsy.