Sandoval Imelda T, Manos Elizabeth J, Van Wagoner Ryan M, Delacruz Richard Glenn C, Edes Kornelia, Winge Dennis R, Ireland Chris M, Jones David A
Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Chem Biol. 2013 Jun 20;20(6):753-63. doi: 10.1016/j.chembiol.2013.05.008.
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.
在使用复杂系统进行药物筛选时，一个主要障碍是难以确定小分子的作用机制靶点。斑马鱼为利用生物体遗传学将发育表型与机制发现相结合提供了一个出色的模型系统。我们对斑马鱼中未表征的小分子进行了基于表型的筛选，这些小分子产生了多种具有潜在遗传相似性的化学诱导表型。具体而言，卡里希诺醇F导致脊索波动、色素形成、造血和神经发育缺陷。这些表型与斑马鱼突变体calamity极为相似，calamity是一种已确立的铜缺乏模型。对卡里希诺醇F作用机制的进一步研究揭示了其铜螯合活性。我们的数据支持卡里希诺醇F的这种作用机制以及斑马鱼作为识别治疗和靶点途径的有效系统的实用性。
