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Zebrafish as tools for drug discovery
Calum A.MacRae14 and Randall T.Peterson36
Abstract | The zebrafish has become a prominent vertebrate model for disease and has already contributed to several examples of successful phenotype-based drug discovery. For the zebrafish to become useful in drug development more broadly, key hurdles must be overcome, including a more comprehensive elucidation of the similarities and differences between human and zebrafish biology. Recent studies have begun to establish the capabilities and limitations of zebrafish for disease modelling, drug screening, target identification, pharmacology, and toxicology. As our understanding increases and as the technologies for manipulating zebrafish improve, it is hoped that the zebrafish will have a key role in accelerating the emergence of precision medicine.
Cardiovascular Medicine and Network Medicine Divisions, Brigham and Womens Hospital, Boston, Massachusetts 02115, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Department of Systems Biology, Harvard
Medical School, Boston, Massachusetts 02115, USA. e-mails: mailto:[email protected]
Web End [email protected]. mailto:[email protected]
Web End =harvard.edu ; mailto:[email protected]
Web End =peterson@cvrc. mailto:[email protected]
Web End =mgh.harvard.edu doi:10.1038/nrd4627 Published online 11 September 2015
We are currently witnessing a resurgence of interest in
phenotype-based screening in drug discovery. Phenotypic effects of small molecules were historically the basis of all drug discovery, but over the past 30years this strategy has been largely replaced by target-based approaches. There is now a growing appreciation that first-in-class drug discovery successes are emerging disproportionately from the remaining phenotype-based efforts. For example, a recent analysis of first-in-class drugs approved between 1999 and 2008 revealed that 62% were discovered by phenotype-based screens, despite the fact that such screens represented only a small subset of the overalltotal1.
Several factors may explain the apparent superiority of phenotype-based approaches over target-based
screening efforts. First, phenotypic screens can discover efficacious drugs in the absence of a validated target. For example, ezetimibe was discovered based on its cholesterol-lowering activity years before NiemannPick C1-like protein 1 (NPC1L1) was validated as a therapeutic target2,3. Second, phenotypic screens can identify compounds that produce a therapeutic effect through simultaneous activity at multiple targets. Thus, amiodarone, which remains the...