A Photohormone for Light-Dependent Control of PPARα in Live Cells

Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in their cis- and trans-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, PPAR alpha and PPAR delta. We have developed a set of highly potent PPAR alpha and PPAR delta targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPAR alpha in its trans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARa activity on and off in a light- and time-dependent fashion.

Automated summary

Photopharmacology enables optical control of biochemical processes using small-molecule photoswitches, with potential for developing drug molecules that can be locally activated to reduce adverse effects. Expanding the photopharmacological arsenal to new members of the PPAR family has shown promising results in selectively activating specific PPAR subtypes in live cells.