Journal
NEPHRON
Volume 137, Issue 4, Pages 268-272Publisher
KARGER
DOI: 10.1159/000476079
Keywords
Drug discovery; Phenotypic screening; Molecular targets; Zebrafish; Acute kidney injury
Categories
Funding
- National Institutes of Health [1RC4DK090770, RO1DK069403-05S1, U24 DK076169, R01 DK069403, R01 DK112652, R01 HD053287, P30 DK079307]
- [P30CA047904]
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The cellular responses that occur following acute kidney injury (AKI) are complex and dynamic, involving multiple cells types and molecular pathways. For this reason, early selection of defined molecular targets for therapeutic intervention is unlikely to be effective in complex in vivo models of AKI, let alone Phase 3 clinical trials in patients with even more complex AKI pathobiology. Phenotypic screening using zebrafish provides an attractive alternative that does not require prior knowledge of molecular targets and may identify compounds that modify multiple targets that might be missed in more traditional target- based screens. In this review, we discuss results of an academic drug discovery campaign that used zebrafish as a primary screening tool to discover compounds with favorable absorption, metabolism, and toxicity that enhance repair when given late after injury in multiple models of AKI. We discuss how this screening campaign is being integrated into a more comprehensive, phenotypic, and target- based screen for lead compound optimization. (C) 2017 S. Karger AG, Basel
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