June 1, 2009;
Simple vertebrate models for chemical genetics and drug discovery screens: lessons from zebrafish and Xenopus.
Chemical genetics uses small molecules to modulate protein function and, in principle, has the potential to perturb any biochemical event in a complex cellular context. The application of chemical genetics to dissect biological processes has become an attractive alternative to mutagenesis screens due to its technical simplicity, inexpensive reagents, and low-startup costs. In vertebrates, only fish and amphibians are amenable to chemical genetic screens. Xenopus frogs share a long evolutionary history with mammals and so represent an excellent model to predict human biology. In this review, we discuss the lessons learned from chemical genetic studies carried out in zebrafish and Xenopus. We highlight how Xenopus can be employed as a convenient first-line animal model at various stages of the drug discovery and development process and comment on how they represent much-needed tools to bridge the gap between traditional in vitro and preclinical mammalian assays in biomedical research and drug development. Developmental Dynamics 238:1287-1308, 2009. (c) 2009 Wiley-Liss, Inc.
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Figure 1. Phylogenetic tree showing the main animal models commonly used in biomedical research and their evolutionary relationship. The divergence times in millions of years ago (Mya) are shown based on multigene and multiprotein studies (Hedges and Kumar,2002; Hedges,2002; Ureta-Vidal et al.,2003). Branch lengths are not proportional to time.Download figure to PowerPoint
Figure 2. Flow diagram of a Xenopus chemical library screen. Compounds are arrayed in multi-well plates and five embryos at stage 15 are added per well. These are incubated for 3 days and then scored for phenotypic changes in comparison to control tadpoles. Examples of some of the possible pigmentation phenotypes observed are shown. Positive hits are independently verified. Reproduced by permission of Royal Society of Chemistry (Tomlinson et al.,2009b).Download figure to PowerPoint
Figure 3. The utility of Xenopus in drug discovery and development. The two broad strategies of drug discovery and development are shown. The target-based strategy requires a functional understanding of the disease pathway to determine target genes or proteins for drug discovery and development. The activity-based strategy selects for drug candidates on the basis of biological activities implicated with a therapeutic benefit. The Xenopus embryos and tadpoles can serve as cheap and efficient bioassay tools at several stages of the drug-discovery process regardless of the strategy chosen. SAR, structure-activity-relationship.Download figure to PowerPoint