Juxtaposition of Chemical and Mutation-Induced Developmental Defects in Zebrafish Reveal a Copper-Chelating Activity for Kalihinol F

•Screened compound libraries using zebrafish to identify modulators of embryogenesis•Reported bioactivity for kalihinol F as inducing a copper-deficient phenotype•Revealed MOA of kalihinol F by juxtaposing phenotype with zebrafish genetic mutants•Identified the kalihinol family of compounds as a class of copper chelators

SummaryA major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper-chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways.

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