A fine-tuned azobenzene for enhanced photopharmacology in vivo
Copyright © 2021 Elsevier Ltd. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Cell chemical biology - 28(2021), 11 vom: 18. Nov., Seite 1648-1663.e16 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gutzeit, Vanessa A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.01.2022 Date Revised 19.11.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2021.02.020 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM322921279 |
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| 245 | 1 | 2 | |a A fine-tuned azobenzene for enhanced photopharmacology in vivo |
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| 500 | |a Date Revised 19.11.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a G protein-coupled receptor | |
| 650 | 4 | |a PORTL | |
| 650 | 4 | |a azobenzene | |
| 650 | 4 | |a calcium signaling | |
| 650 | 4 | |a dorsal root ganglia | |
| 650 | 4 | |a metabotropic glutamate receptor | |
| 650 | 4 | |a optogenetics | |
| 650 | 4 | |a photopharmacology | |
| 650 | 4 | |a potassium channel | |
| 650 | 4 | |a prefrontal cortex | |
| 650 | 4 | |a working memory | |
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| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Potassium Channels |2 NLM | |
| 650 | 7 | |a Receptors, Metabotropic Glutamate |2 NLM | |
| 650 | 7 | |a azobenzene |2 NLM | |
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| 700 | 1 | |a Acosta-Ruiz, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Munguba, Hermany |e verfasserin |4 aut | |
| 700 | 1 | |a Häfner, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Landra-Willm, Arnaud |e verfasserin |4 aut | |
| 700 | 1 | |a Mathes, Bettina |e verfasserin |4 aut | |
| 700 | 1 | |a Mony, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Yarotski, Dzianis |e verfasserin |4 aut | |
| 700 | 1 | |a Börjesson, Karl |e verfasserin |4 aut | |
| 700 | 1 | |a Liston, Conor |e verfasserin |4 aut | |
| 700 | 1 | |a Sandoz, Guillaume |e verfasserin |4 aut | |
| 700 | 1 | |a Levitz, Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Broichhagen, Johannes |e verfasserin |4 aut | |
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