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Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177

BACKGROUND: Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC(1)) as reported in several experimental settings. As such, MC(1) can be a viable target for the development of new therapies that...

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Autores principales: Garrido-Mesa, Jose, Thomas, Bethan Lynne, Dodd, John, Spana, Carl, Perretti, Mauro, Montero-Melendez, Trinidad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9730523/
https://www.ncbi.nlm.nih.gov/pubmed/36505403
http://dx.doi.org/10.3389/fimmu.2022.1078678
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author Garrido-Mesa, Jose
Thomas, Bethan Lynne
Dodd, John
Spana, Carl
Perretti, Mauro
Montero-Melendez, Trinidad
author_facet Garrido-Mesa, Jose
Thomas, Bethan Lynne
Dodd, John
Spana, Carl
Perretti, Mauro
Montero-Melendez, Trinidad
author_sort Garrido-Mesa, Jose
collection PubMed
description BACKGROUND: Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC(1)) as reported in several experimental settings. As such, MC(1) can be a viable target for the development of new therapies that mimic endogenous pro-resolving mediators. The aim of this study was to assess the immunopharmacology of a selective MC(1) agonist (PL8177) in vitro and in a mouse model of inflammatory arthritis. METHODS: PL8177 and the natural agonist αMSH were tested for activation of mouse and human Melanocortin receptors (MC(1,3,4,5)), monitoring cAMP accumulation and ERK1/2 phosphorylation, using transiently transfected HEK293A cells. The anti-inflammatory and pro-resolving effects of PL8177 and αMSH were evaluated using mouse peritoneal Macrophages. Finally, a model of K/BxN serum transfer induced arthritis was used to determine the in vivo potential of PL8177. RESULTS: PL8177 activates mouse and human MC(1) with apparent EC(50) values of 0.01 and 1.49 nM, respectively, using the cAMP accumulation assay. Similar profiles were observed for the induction of ERK phosphorylation (EC(50): 0.05 and 1.39 nM). PL8177 displays pro-resolving activity (enhanced Macrophage efferocytosis) and counteracts the inflammatory profile of zymosan-stimulated macrophages, reducing the release of IL-1β, IL-6, TNF-α and CCL-2. In the context of joint inflammation, PL8177 (3mg/kg i.p.) reduces clinical score, paw swelling and incidence of severe disease as well as the recruitment of immune cells into the arthritic joint. CONCLUSION: These results demonstrate that the MC(1) agonism with PL8177 affords therapeutic effects in inflammatory conditions including arthritis. SIGNIFICANCE: Drugs targeting the Melanocortin system have emerged as promising therapeutics for several conditions including inflammation or obesity. Multiple candidates are under clinical development, and some have already reached approval. Here we present the characterization of a novel drug candidate, PL8177, selective for the Melanocortin 1 receptor (MC(1)), demonstrating its selectivity profile on cAMP and ERK1/2 phosphorylation signaling pathways, of relevance as selective drugs will translate into lesser off-target effect. PL8177 also demonstrated, not only anti-inflammatory activity, but pro-resolving actions due to its ability to enhance efferocytosis (i.e. the phagocytosis of apoptotic cells), endowing this molecule with therapeutic advantages compared to classical anti-inflammatory drugs. Using a mouse model of inflammatory arthritis, the compound demonstrated in vivo efficacy by reducing clinical score, paw swelling and overall disease severity. Taken together, these results present Melanocortin-based therapies, and specifically targeting MC(1) receptor, as a promising strategy to manage chronic inflammatory diseases.
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spelling pubmed-97305232022-12-09 Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177 Garrido-Mesa, Jose Thomas, Bethan Lynne Dodd, John Spana, Carl Perretti, Mauro Montero-Melendez, Trinidad Front Immunol Immunology BACKGROUND: Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC(1)) as reported in several experimental settings. As such, MC(1) can be a viable target for the development of new therapies that mimic endogenous pro-resolving mediators. The aim of this study was to assess the immunopharmacology of a selective MC(1) agonist (PL8177) in vitro and in a mouse model of inflammatory arthritis. METHODS: PL8177 and the natural agonist αMSH were tested for activation of mouse and human Melanocortin receptors (MC(1,3,4,5)), monitoring cAMP accumulation and ERK1/2 phosphorylation, using transiently transfected HEK293A cells. The anti-inflammatory and pro-resolving effects of PL8177 and αMSH were evaluated using mouse peritoneal Macrophages. Finally, a model of K/BxN serum transfer induced arthritis was used to determine the in vivo potential of PL8177. RESULTS: PL8177 activates mouse and human MC(1) with apparent EC(50) values of 0.01 and 1.49 nM, respectively, using the cAMP accumulation assay. Similar profiles were observed for the induction of ERK phosphorylation (EC(50): 0.05 and 1.39 nM). PL8177 displays pro-resolving activity (enhanced Macrophage efferocytosis) and counteracts the inflammatory profile of zymosan-stimulated macrophages, reducing the release of IL-1β, IL-6, TNF-α and CCL-2. In the context of joint inflammation, PL8177 (3mg/kg i.p.) reduces clinical score, paw swelling and incidence of severe disease as well as the recruitment of immune cells into the arthritic joint. CONCLUSION: These results demonstrate that the MC(1) agonism with PL8177 affords therapeutic effects in inflammatory conditions including arthritis. SIGNIFICANCE: Drugs targeting the Melanocortin system have emerged as promising therapeutics for several conditions including inflammation or obesity. Multiple candidates are under clinical development, and some have already reached approval. Here we present the characterization of a novel drug candidate, PL8177, selective for the Melanocortin 1 receptor (MC(1)), demonstrating its selectivity profile on cAMP and ERK1/2 phosphorylation signaling pathways, of relevance as selective drugs will translate into lesser off-target effect. PL8177 also demonstrated, not only anti-inflammatory activity, but pro-resolving actions due to its ability to enhance efferocytosis (i.e. the phagocytosis of apoptotic cells), endowing this molecule with therapeutic advantages compared to classical anti-inflammatory drugs. Using a mouse model of inflammatory arthritis, the compound demonstrated in vivo efficacy by reducing clinical score, paw swelling and overall disease severity. Taken together, these results present Melanocortin-based therapies, and specifically targeting MC(1) receptor, as a promising strategy to manage chronic inflammatory diseases. Frontiers Media S.A. 2022-11-24 /pmc/articles/PMC9730523/ /pubmed/36505403 http://dx.doi.org/10.3389/fimmu.2022.1078678 Text en Copyright © 2022 Garrido-Mesa, Thomas, Dodd, Spana, Perretti and Montero-Melendez 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
Garrido-Mesa, Jose
Thomas, Bethan Lynne
Dodd, John
Spana, Carl
Perretti, Mauro
Montero-Melendez, Trinidad
Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title_full Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title_fullStr Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title_full_unstemmed Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title_short Pro-resolving and anti-arthritic properties of the MC(1) selective agonist PL8177
title_sort pro-resolving and anti-arthritic properties of the mc(1) selective agonist pl8177
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9730523/
https://www.ncbi.nlm.nih.gov/pubmed/36505403
http://dx.doi.org/10.3389/fimmu.2022.1078678
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