chapter  7
The Role of Zebrash in the Future of Natural Product Discovery
Pages 10

Plants have served humans as a living pharmacy for thousands of years and continue to do so today for the large majority of the world’s population. 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. Nevertheless, the related disciplines of pharmacognosy, phytochemistry, and natural product discovery have experienced a signicant decline within the past two decades, primarily due to their relative incompatibility with the current drug discovery paradigm. Conversely, important technological developments within the past 10 years are now being used to address the primary bottleneck of natural product discovery-namely, the bioassay-guided isolation of pure compounds from complex natural matrices. These developments include advances in chromatographic separation, including microfractionation methods based on improved high-performance liquid chromatography (HPLC) techniques, as well as the increasing sophistication of hyphenated techniques such as HPLC-solid-phase extraction-nuclear magnetic resonance (HPLC-SPE-NMR) to enable online or at-line structural elucidation for rapid dereplication. Ultimately, the ability of these new analytical methods to

7.1 Introduction .................................................................................................. 137 7.2 Plant-Based Drug Discovery: From Early Evolution to Modern Medicine .....138 7.3 Zebrash: An In Vivo, High-throughput, Microgram-Scale Bioassay Platform ......................................................................................... 139 7.4 Zebrash Bioassay-Guided Fractionation .................................................... 141 7.5 In Vivo Structure-Activity Relationship Studies .......................................... 142 7.6 In Vivo Toxicity Assays Using Zebrash ...................................................... 143 7.7 In Vivo Validation and Standardization of Plant-Derived Medicines .......... 144 References .............................................................................................................. 144

revitalize the eld of natural product discovery will depend on the biomedical relevance of the bioassays they are linked with. In this context, the recent emergence of in vivo, microgram-scale, high-throughput assays based on zebrash embryos and larvae represent a unique opportunity for the systematic identication of bioactive natural products. Zebrash offer the ability to rapidly evaluate-at a very early stage in the drug discovery process-not only the therapeutic potential of natural products, but also their potential hepato-, cardio-, and neurotoxicities. Due to the requirement for only microgram quantities of compounds to be tested, in vivo assays based on zebrash are useful not only for bioassay-guided isolation, but also for the subsequent derivatization of bioactive natural products prioritized for further development as drug discovery leads. Beyond the scope of modern medicine, zebrash bioassays can also contribute to the validation of plant-based traditional medicines, to the eludication of their active constituents, and subsequently to their standardization and optimization.