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The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine
The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482581/ https://www.ncbi.nlm.nih.gov/pubmed/32973504 http://dx.doi.org/10.3389/fphar.2020.01253 |
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author | Beck, Tyler C. Beck, Kyle R. Holloway, Calvin B. Hemings, Richard A. Dix, Thomas A. Norris, Russell A. |
author_facet | Beck, Tyler C. Beck, Kyle R. Holloway, Calvin B. Hemings, Richard A. Dix, Thomas A. Norris, Russell A. |
author_sort | Beck, Tyler C. |
collection | PubMed |
description | The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19. |
format | Online Article Text |
id | pubmed-7482581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74825812020-09-23 The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine Beck, Tyler C. Beck, Kyle R. Holloway, Calvin B. Hemings, Richard A. Dix, Thomas A. Norris, Russell A. Front Pharmacol Pharmacology The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19. Frontiers Media S.A. 2020-08-28 /pmc/articles/PMC7482581/ /pubmed/32973504 http://dx.doi.org/10.3389/fphar.2020.01253 Text en Copyright © 2020 Beck, Beck, Holloway, Hemings, Dix and Norris http://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 | Pharmacology Beck, Tyler C. Beck, Kyle R. Holloway, Calvin B. Hemings, Richard A. Dix, Thomas A. Norris, Russell A. The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title | The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title_full | The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title_fullStr | The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title_full_unstemmed | The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title_short | The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine |
title_sort | c-c chemokine receptor type 4 is an immunomodulatory target of hydroxychloroquine |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482581/ https://www.ncbi.nlm.nih.gov/pubmed/32973504 http://dx.doi.org/10.3389/fphar.2020.01253 |
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