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

J Med Chem. 2020 Oct 8;63(19):10908-10920. doi: 10.1021/acs.jmedchem.0c00654. Epub 2020 Sep 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Light*
  • Molecular Docking Simulation
  • PPAR gamma / agonists*
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / metabolism

Substances

  • PPAR gamma
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Retinoic Acid
  • farnesoid X-activated receptor