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

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posted on 21.09.2020 by Konstantin Hinnah, Sabine Willems, Johannes Morstein, Jan Heering, Felix W. W. Hartrampf, Johannes Broichhagen, Philipp Leippe, Daniel Merk, Dirk Trauner
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 PPARγ 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 PPARγ preferentially in its light-activated cis-configuration.