Cell Chem Biol. 2021 Mar 13;S2451-9456(21)00105-7. doi: 10.1016/j.chembiol.2021.02.020. Online ahead of print.
Vanessa A Gutzeit 1, Amanda Acosta-Ruiz 2, Hermany Munguba 3, Stephanie Häfner 4, Arnaud Landra-Willm 4, Bettina Mathes 5, Jürgen Mony 6, Dzianis Yarotski 5, Karl Börjesson 6, Conor Liston 7, Guillaume Sandoz 4, Joshua Levitz 8, Johannes Broichhagen 9
Affiliations
1 Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.
2 Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.
3 Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
4 Université Cote d’Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France.
5 Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
6 Department of Chemistry and Molecular Biology, University of Gothenburg, 41296 Gothenburg, Sweden.
7 Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
8 Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: jtl2003@med.cornell.edu.
9 Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany; Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany. Electronic address: broichhagen@fmp-berlin.de.
Abstract
Despite the power of photopharmacology for interrogating signaling proteins, many photopharmacological systems are limited by their efficiency, speed, or spectral properties. Here, we screen a library of azobenzene photoswitches and identify a urea-substituted “azobenzene-400” core that offers bistable switching between cis and trans with improved kinetics, light sensitivity, and a red-shift. We then focus on the metabotropic glutamate receptors (mGluRs), neuromodulatory receptors that are major pharmacological targets. Synthesis of “BGAG12,400,” a photoswitchable orthogonal, remotely tethered ligand (PORTL), enables highly efficient, rapid optical agonism following conjugation to SNAP-tagged mGluR2 and permits robust optical control of mGluR1 and mGluR5 signaling. We then produce fluorophore-conjugated branched PORTLs to enable dual imaging and manipulation of mGluRs and highlight their power in ex vivo slice and in vivo behavioral experiments in the mouse prefrontal cortex. Finally, we demonstrate the generalizability of our strategy by developing an improved soluble, photoswitchable pore blocker for potassium channels.
PMID: 33735619
DOI: 10.1016/j.chembiol.2021.02.020