A Photohormone for Light-Dependent Control of PPARα in Live Cells.
A Photohormone for Light-Dependent Control of PPARα in Live Cells.
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用于活细胞中 PPARα 光依赖性控制的光激素。
DOI：
10.1021/acs.jmedchem.1c00810
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发表时间：
2021
影响因子：
7.3
通讯作者：
Merk,Daniel
中科院分区：
文献类型：
--
作者：
Willems,Sabine;Morstein,Johannes;Hinnah,Konstantin;Trauner,Dirk;Merk,Daniel
光药理学使得能够使用在其顺式和反式构象中表现出不同生物活性的小分子光开关来光学控制若干生化过程。此类工具化合物可以对生物信号进行高度时空控制，并且该方法还有望开发可以局部激活以减少靶点介导的不良反应的药物分子。在此，我们将药物库扩展到过氧化物酶体增殖物激活受体（PPAR）家族的两个新成员，PPARα和PPARδ。我们已经开发了一套高效的PPARα和PPARδ靶向光激素，这些光激素来源于可被光灭活的弱泛-PPAR激动剂GL 479。光敏剂6选择性激活其反式构象的PPARα，对相关的PPAR亚型具有高选择性，并在活细胞中以光和时间依赖性的方式打开和关闭PPARα活性。
Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in theircis- andtrans-conformations. Such tool compounds allow for high spatiotemporal control of biological signaling, and the approach also holds promise for the development of drug molecules that can be locally activated to reduce target-mediated adverse effects. Herein, we present the expansion of the photopharmacological arsenal to two new members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα and PPARδ. We have developed a set of highly potent PPARα and PPARδ targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone6selectively activated PPARα in itstrans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARα activity on and off in a light- and time-dependent fashion.