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, PPARα
and PPARδ. We have developed a set of highly potent PPARα
and PPARδ targeting photohormones derived from the weak pan-PPAR
agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPARα in its trans-conformation with high selectivity over the related PPAR subtypes
and was used in live cells to switch PPARα activity on and off
in a light- and time-dependent fashion.