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Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation

Chemokine G-protein coupled receptors are validated drug targets for many diseases, including cancer, neurological, and inflammatory disorders. Despite much time and effort spent on therapeutic development, very few chemokine receptor antagonists are approved for clinical use. Among potential reason...

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Autores principales: Grudzien, Patrick, Neufeld, Henry, Ebe Eyenga, Mbasogo, Gaponenko, Vadim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420067/
https://www.ncbi.nlm.nih.gov/pubmed/37575219
http://dx.doi.org/10.3389/fimmu.2023.1184014
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author Grudzien, Patrick
Neufeld, Henry
Ebe Eyenga, Mbasogo
Gaponenko, Vadim
author_facet Grudzien, Patrick
Neufeld, Henry
Ebe Eyenga, Mbasogo
Gaponenko, Vadim
author_sort Grudzien, Patrick
collection PubMed
description Chemokine G-protein coupled receptors are validated drug targets for many diseases, including cancer, neurological, and inflammatory disorders. Despite much time and effort spent on therapeutic development, very few chemokine receptor antagonists are approved for clinical use. Among potential reasons for the slow progress in developing chemokine receptor inhibitors, antagonist tolerance, a progressive reduction in drug efficacy after repeated administration, is likely to play a key role. The mechanisms leading to antagonist tolerance remain poorly understood. In many cases, antagonist tolerance is accompanied by increased receptor concentration on the cell surface after prolonged exposure to chemokine receptor antagonists. This points to a possible role of altered receptor internalization and presentation on the cell surface, as has been shown for agonist (primarily opioid) tolerance. In addition, examples of antagonist tolerance in the context of other G-protein coupled receptors suggest the involvement of noncanonical signal transduction in opposing the effects of the antagonists. In this review, we summarize the available progress and challenges in therapeutic development of chemokine receptor antagonists, describe the available knowledge about antagonist tolerance, and propose new avenues for future investigation of this important phenomenon. Furthermore, we highlight the modern methodologies that have the potential to reveal novel mechanisms leading to antagonist tolerance and to propel the field forward by advancing the development of potent “tolerance-free” antagonists of chemokine receptors.
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spelling pubmed-104200672023-08-12 Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation Grudzien, Patrick Neufeld, Henry Ebe Eyenga, Mbasogo Gaponenko, Vadim Front Immunol Immunology Chemokine G-protein coupled receptors are validated drug targets for many diseases, including cancer, neurological, and inflammatory disorders. Despite much time and effort spent on therapeutic development, very few chemokine receptor antagonists are approved for clinical use. Among potential reasons for the slow progress in developing chemokine receptor inhibitors, antagonist tolerance, a progressive reduction in drug efficacy after repeated administration, is likely to play a key role. The mechanisms leading to antagonist tolerance remain poorly understood. In many cases, antagonist tolerance is accompanied by increased receptor concentration on the cell surface after prolonged exposure to chemokine receptor antagonists. This points to a possible role of altered receptor internalization and presentation on the cell surface, as has been shown for agonist (primarily opioid) tolerance. In addition, examples of antagonist tolerance in the context of other G-protein coupled receptors suggest the involvement of noncanonical signal transduction in opposing the effects of the antagonists. In this review, we summarize the available progress and challenges in therapeutic development of chemokine receptor antagonists, describe the available knowledge about antagonist tolerance, and propose new avenues for future investigation of this important phenomenon. Furthermore, we highlight the modern methodologies that have the potential to reveal novel mechanisms leading to antagonist tolerance and to propel the field forward by advancing the development of potent “tolerance-free” antagonists of chemokine receptors. Frontiers Media S.A. 2023-07-28 /pmc/articles/PMC10420067/ /pubmed/37575219 http://dx.doi.org/10.3389/fimmu.2023.1184014 Text en Copyright © 2023 Grudzien, Neufeld, Ebe Eyenga and Gaponenko 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 Immunology
Grudzien, Patrick
Neufeld, Henry
Ebe Eyenga, Mbasogo
Gaponenko, Vadim
Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title_full Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title_fullStr Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title_full_unstemmed Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title_short Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
title_sort development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420067/
https://www.ncbi.nlm.nih.gov/pubmed/37575219
http://dx.doi.org/10.3389/fimmu.2023.1184014
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