Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation.
antagonist
antagonist tolerance
chemokine receptors
clustering
oligomerization
signaling
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
10
03
2023
accepted:
27
06
2023
medline:
15
8
2023
pubmed:
14
8
2023
entrez:
14
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37575219
doi: 10.3389/fimmu.2023.1184014
pmc: PMC10420067
doi:
Substances chimiques
Receptors, Chemokine
0
Receptors, G-Protein-Coupled
0
Analgesics, Opioid
0
Chemokines
0
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1184014Informations de copyright
Copyright © 2023 Grudzien, Neufeld, Ebe Eyenga and Gaponenko.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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