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Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor
[Image: see text] G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227462/ https://www.ncbi.nlm.nih.gov/pubmed/34115935 http://dx.doi.org/10.1021/jacs.1c02586 |
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author | Donthamsetti, Prashant Konrad, David B. Hetzler, Belinda Fu, Zhu Trauner, Dirk Isacoff, Ehud Y. |
author_facet | Donthamsetti, Prashant Konrad, David B. Hetzler, Belinda Fu, Zhu Trauner, Dirk Isacoff, Ehud Y. |
author_sort | Donthamsetti, Prashant |
collection | PubMed |
description | [Image: see text] G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G(i/o)-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins. |
format | Online Article Text |
id | pubmed-8227462 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-82274622021-06-25 Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor Donthamsetti, Prashant Konrad, David B. Hetzler, Belinda Fu, Zhu Trauner, Dirk Isacoff, Ehud Y. J Am Chem Soc [Image: see text] G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G(i/o)-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins. American Chemical Society 2021-06-11 2021-06-23 /pmc/articles/PMC8227462/ /pubmed/34115935 http://dx.doi.org/10.1021/jacs.1c02586 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Donthamsetti, Prashant Konrad, David B. Hetzler, Belinda Fu, Zhu Trauner, Dirk Isacoff, Ehud Y. Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor |
title | Selective
Photoswitchable Allosteric Agonist of a
G Protein-Coupled Receptor |
title_full | Selective
Photoswitchable Allosteric Agonist of a
G Protein-Coupled Receptor |
title_fullStr | Selective
Photoswitchable Allosteric Agonist of a
G Protein-Coupled Receptor |
title_full_unstemmed | Selective
Photoswitchable Allosteric Agonist of a
G Protein-Coupled Receptor |
title_short | Selective
Photoswitchable Allosteric Agonist of a
G Protein-Coupled Receptor |
title_sort | selective
photoswitchable allosteric agonist of a
g protein-coupled receptor |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227462/ https://www.ncbi.nlm.nih.gov/pubmed/34115935 http://dx.doi.org/10.1021/jacs.1c02586 |
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