Identification of a Novel Retinoid by Small Molecule Screening with Zebrafish Embryos
Identification of a Novel Retinoid by Small Molecule Screening with Zebrafish Embryos
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DOI：
10.1371/journal.pone.0001947
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发表时间：
2008-04-09
期刊：
影响因子：
3.7
通讯作者：
Peterson, Randall T.
中科院分区：
文献类型：
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作者：
Sachidanandan, Chetana;Yeh, Jing-Ruey J.;Peterson, Randall T.
小分子在描述参与胚胎发育和疾病病理的分子途径方面发挥了重要作用。对生物过程的新型小分子调节剂的需求已经推动了许多大型不同文库的靶向筛选。然而，由于这些筛选的特定焦点，这些文库的大部分生物活性潜力仍未得到利用。为了鉴定出更高比例的具有有趣生物活性的化合物，我们筛选了一个不同的合成文库，用于干扰斑马鱼胚胎中任何多个器官的发育。我们发现了影响心脏、脉管系统、大脑和身体轴等多种结构发育的小分子。我们利用之前已知的视黄酸在前后（a -p）模式中的作用来确定DTAB的靶标，DTAB是一种在斑马鱼胚胎中导致a -p轴缩短的化合物。我们发现DTAB是一种对视黄酸受体γ和β具有选择性活性的类视黄酸。因此，利用小分子进行斑马鱼发育筛选，不仅可以在庞大的化学文库中鉴定具有多种生物活性的化合物，还可以促进这些生物活性分子靶通路的鉴定。
Small molecules have played an important role in delineating molecular pathways involved in embryonic development and disease pathology. The need for novel small molecule modulators of biological processes has driven a number of targeted screens on large diverse libraries. However, due to the specific focus of such screens, the majority of the bioactive potential of these libraries remains unharnessed. In order to identify a higher proportion of compounds with interesting biological activities, we screened a diverse synthetic library for compounds that perturb the development of any of the multiple organs in zebrafish embryos. We identified small molecules that affect the development of a variety of structures such as heart, vasculature, brain, and body-axis. We utilized the previously known role of retinoic acid in anterior-posterior (A-P) patterning to identify the target of DTAB, a compound that caused A-P axis shortening in the zebrafish embryo. We show that DTAB is a retinoid with selective activity towards retinoic acid receptors gamma and beta. Thus, conducting zebrafish developmental screens using small molecules will not only enable the identification of compounds with diverse biological activities in a large chemical library but may also facilitate the identification of the target pathways of these biologically active molecules.