title: Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F.
abstract: A 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.
authors.affiliation: Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Imelda T
authors.initials: IT
authors.lastname: Sandoval
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Manos
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Van Wagoner
authors.forename: Richard Glenn C
authors.initials: RG
authors.lastname: Delacruz
authors.forename: Kornelia
authors.initials: K
authors.lastname: Edes
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Winge
authors.forename: Chris M
authors.initials: CM
authors.lastname: Ireland
authors.forename: David A
authors.initials: DA
authors.lastname: Jones
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry* / Q000633:toxicity; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D004224:Diterpenes / Q000737:chemistry* / Q000633:toxicity; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D009154:Mutation; D009570:Nitriles / Q000737:chemistry* / Q000633:toxicity; D009672:Notochord / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D004224:Diterpenes; D009570:Nitriles; C488364:kalihinol F; D003300:Copper; C029892:cupric chloride