Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype1,2. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans3,4,5. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly.
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This work was supported by grants from the National Institutes of Health, by the Ned Sahin Research Fund for Restoring Developmental Plasticity and by a sponsored research agreement with Novartis Institutes for Biomedical Research. S.Y.S. is a Physician-Postdoctoral Fellow and S.L.S. is an Investigator at the Howard Hughes Medical Institute. S.L.S. is also supported by a grant from the Donald W. Reynolds Cardiovascular Clinical Research Center (University of Texas Southwestern Medical Center).
R.T.P. and C.A.M. receive research funding through a sponsored research agreement with Novartis Institutes for BioMedical Research.
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Peterson, R., Shaw, S., Peterson, T. et al. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 22, 595–599 (2004). https://doi.org/10.1038/nbt963