Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

被引：28

作者：

Hinnah, Konstantin ^{[1
]}

Willems, Sabine ^{[2
]}

Morstein, Johannes ^{[1
]}

Heering, Jan ^{[3
]}

Hartrampf, Felix W. W. ^{[4
,5
]}

Broichhagen, Johannes ^{[4
,5
]}

Leippe, Philipp ^{[4
,5
]}

Merk, Daniel ^{[2
,4
,5
]}

Trauner, Dirk ^{[1
]}

机构：

[1] NYU, Dept Chem, 4 Washington Pl, New York, NY 10003 USA

[2] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt, Germany

[3] Fraunhofer Inst Mol Biol & Appl Ecol IME, Branch Translat Med & Pharmacol TMP, D-60596 Frankfurt, Germany

[4] Ludwig Maximilians Univ Munchen, Dept Chem, D-81377 Munich, Germany

[5] Ludwig Maximilians Univ Munchen, Ctr Integrated Prot Sci CIPSM, D-81377 Munich, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 19期

基金：

美国国家卫生研究院;

关键词：

NUCLEAR RECEPTORS; DISCOVERY; ACID; INHIBITORS; AGONISTS; ANALOGS; LIGAND; ROLES;

D O I：

10.1021/acs.jmedchem.0c00654

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor gamma (PPAR gamma). Based on known PPAR gamma ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed AzoGW1929 and AzoRosi, which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of AzoRosi resulted in the photohormone AzoRosi-4, which bound and activated PPAR gamma preferentially in its light-activated cis-configuration.

引用

页码：10908 / 10920

页数：13

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