A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity.
A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity.
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DOI：
10.1371/journal.pone.0010004
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发表时间：
2010-04-02
期刊：
影响因子：
3.7
通讯作者：
Evans T
中科院分区：
文献类型：
--
作者：
Das BC;McCartin K;Liu TC;Peterson RT;Evans T
类维生素A在整个生命过程中调节关键的发育途径，并具有分化治疗的潜在用途。通过将新的化学反应与使用斑马鱼胚胎模型的筛选相结合，应该有可能识别新的类维生素A。我们通过酰胺偶联法合成了新的维甲酸类似物和衍生物，产率为80-92%。这些化合物的一个小文库在活的斑马鱼胚胎中筛选生物活性。我们发现，一些结构相关的化合物显着影响发展。根据暴露时间产生不同的表型，我们描述了一种化合物（BT 10），在受精后1天添加时会产生特定的心血管缺陷。与维甲酸（ATRA）相比，BT 10显示出类似但不相同的胚胎基因表达模式的变化，这些基因是类维生素A通路的已知靶点。报告基因测定确定BT 10与所有三种RAR受体亚型相互作用，但在所有测试浓度下对RXR受体没有活性。我们的筛选已经确定了一种新的类维生素A受体的特异性。该先导化合物可用于操纵类维生素A信号网络的组分，并且可进一步衍生化以增强活性。
Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80–92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested. Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity.
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影响因子：
3.7
作者：
Sachidanandan, Chetana;Yeh, Jing-Ruey J.;Peterson, Randall T.
通讯作者：
Peterson, Randall T.
影响因子：
4.2
作者：
Zile, MH
通讯作者：
Zile, MH
影响因子：
3.5
作者：
Schreiber, SL
通讯作者：
Schreiber, SL
影响因子：
3.2
作者：
Petrie, Kevin;Zelent, Arthur;Waxman, Samuel
通讯作者：
Waxman, Samuel
DOI：
10.1073/pnas.97.24.12965
发表时间：
2000-11-21
影响因子：
11.1
作者：
Peterson, RT;Link, BA;Schreiber, SL
通讯作者：
Schreiber, SL