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

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.