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Intracellular VHHs to monitor and modulate GPCR signaling

Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies prima...

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Autores principales: Raynaud, Pauline, Gauthier, Camille, Jugnarain, Vinesh, Jean-Alphonse, Frédéric, Reiter, Eric, Bruneau, Gilles, Crépieux, Pascale
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708903/
https://www.ncbi.nlm.nih.gov/pubmed/36465650
http://dx.doi.org/10.3389/fendo.2022.1048601
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author Raynaud, Pauline
Gauthier, Camille
Jugnarain, Vinesh
Jean-Alphonse, Frédéric
Reiter, Eric
Bruneau, Gilles
Crépieux, Pascale
author_facet Raynaud, Pauline
Gauthier, Camille
Jugnarain, Vinesh
Jean-Alphonse, Frédéric
Reiter, Eric
Bruneau, Gilles
Crépieux, Pascale
author_sort Raynaud, Pauline
collection PubMed
description Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010’s. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or β-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery.
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spelling pubmed-97089032022-12-01 Intracellular VHHs to monitor and modulate GPCR signaling Raynaud, Pauline Gauthier, Camille Jugnarain, Vinesh Jean-Alphonse, Frédéric Reiter, Eric Bruneau, Gilles Crépieux, Pascale Front Endocrinol (Lausanne) Endocrinology Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010’s. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or β-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery. Frontiers Media S.A. 2022-11-16 /pmc/articles/PMC9708903/ /pubmed/36465650 http://dx.doi.org/10.3389/fendo.2022.1048601 Text en Copyright © 2022 Raynaud, Gauthier, Jugnarain, Jean-Alphonse, Reiter, Bruneau and Crépieux https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Raynaud, Pauline
Gauthier, Camille
Jugnarain, Vinesh
Jean-Alphonse, Frédéric
Reiter, Eric
Bruneau, Gilles
Crépieux, Pascale
Intracellular VHHs to monitor and modulate GPCR signaling
title Intracellular VHHs to monitor and modulate GPCR signaling
title_full Intracellular VHHs to monitor and modulate GPCR signaling
title_fullStr Intracellular VHHs to monitor and modulate GPCR signaling
title_full_unstemmed Intracellular VHHs to monitor and modulate GPCR signaling
title_short Intracellular VHHs to monitor and modulate GPCR signaling
title_sort intracellular vhhs to monitor and modulate gpcr signaling
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708903/
https://www.ncbi.nlm.nih.gov/pubmed/36465650
http://dx.doi.org/10.3389/fendo.2022.1048601
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