TY - JOUR
T1 - Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ(PPARγ)
AU - Hinnah, Konstantin
AU - Willems, Sabine
AU - Morstein, Johannes
AU - Heering, Jan
AU - Hartrampf, Felix W.W.
AU - Broichhagen, Johannes
AU - Leippe, Philipp
AU - Merk, Daniel
AU - Trauner, Dirk
N1 - Funding Information:
J. M. and K. H. thank the German Academic Scholarship Foundation for a fellowship, and J. M. thanks the New York University for a MacCracken fellowship and a Margaret and Herman Sokol fellowship. D.M. is grateful for financial support by the Aventis Foundation. We thank Dr. Lisa Suwandhi and Dr. Siegfried Ussar from Helmholtz Zentrum München for experimental support in the initial stages of the project and Dr. Peter Mayer from LMU for X-ray crystallography data. We thank Boehringer Ingelheim for generous financial support. This work was supported by the National Institutes of Health (Grant R01NS108151-01).
Funding Information:
J. M. and K. H. thank the German Academic Scholarship Foundation for a fellowship, and J. M. thanks the New York University for a MacCracken fellowship and a Margaret and Herman Sokol fellowship. D.M. is grateful for financial support by the Aventis Foundation. We thank Dr. Lisa Suwandhi and Dr. Siegfried Ussar from Helmholtz Zentrum Munchen for experimental support in the initial stages of the project and Dr. Peter Mayer from LMU for X-ray crystallography data. We thank Boehringer Ingelheim for generous financial support. This work was supported by the National Institutes of Health (Grant R01NS108151-01).
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/10/8
Y1 - 2020/10/8
N2 - 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 γ(PPARγ). Based on known PPARγligands (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 PPARγpreferentially in its light-activated cis-configuration.
AB - 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 γ(PPARγ). Based on known PPARγligands (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 PPARγpreferentially in its light-activated cis-configuration.
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U2 - 10.1021/acs.jmedchem.0c00654
DO - 10.1021/acs.jmedchem.0c00654
M3 - Article
C2 - 32886507
AN - SCOPUS:85092749552
SN - 0022-2623
VL - 63
SP - 10908
EP - 10920
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -