Laboratory for Molecular Biodiscovery
The Lab for Molecular Biodiscovery at the University of Leuven (Belgium) is interested in the identification and validation of novel small molecules with significant pharmacological potential using a zebrafish-based platform, with a special interest in small molecules from natural sources. The lab has major efforts underway to find hits with novel chemical structures in the areas of epilepsy and BMP/Wnt signaling.
Small Molecules from Natural Sources
Small molecules from natural sources are recognized as evolved, privileged structures with greater likelihood than many synthetic compounds to exhibit specific bioactivities. For example, 73% of cancer therapeutics approved to date are either natural products or derivatives thereof.
Drug discovery with zebrafish
Because of the low throughput of conventional in vivo models such as mice and rats, in addition to the relatively large amounts of compound required for testing in these systems, in vivo assay-guided fractionation is currently not a widely-used approach for the discovery of drug-like natural products.
Novel opportunities for in vivo natural product discovery have arisen through the recent emergence of zebrafish as an effective model system for the identification of disease-relevant genes and bioactive small molecules.
Large-scale genetic screens in zebrafish carried out since the early 1990s have led to the identification of therapeutically relevant genes in several indication areas, including cardiovascular, neurological, gastrointestinal, musculoskeletal, and metabolic disorders. In addition, small-molecule screens carried out in zebrafish within the past decade have confirmed the ability of this model system to identify bioactive compounds in a target-independent manner, thereby enabling the discovery of novel mechanisms of action.
Primary advantages of zebrafish
The primary advantages of zebrafish for drug discovery include their high genetic, physiologic, and pharmacologic similarity with humans, as well as the small size, optical transparency, rapid development, and large numbers of their embryos and larvae, which are the primary system for experimental analysis. Because of their small size (1 to 5 mm), zebrafish embryos and larvae are compatible with microtiter plates for screening, thereby requiring only microgram amounts of each extract, fraction, or compound to be tested.
Because of the high fecundity of zebrafish, large numbers of embryos and larvae can be produced and analyzed in a more cost-effective manner than, for example, mice and rats. Combined, these features define zebrafish as an ideal in vivo model for the systematic identification of bioactive natural products with therapeutic potential.
The lab recently became coordinator of the PharmaSea consortium, a 9.5 Mio. EUR EU-funded project of 24 partners from 13 countries to isolate and identify biological activity for novel compound structural classes from marine microorganisms derived from extreme biomes (e.g. deep (8 km below sea level) waters, hot and cold vents) (for more info: http://www.pharma-sea.eu/)