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Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory...

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Autores principales: Wang, Zhiyu, Wang, Yanfei, Vilekar, Prachi, Yang, Seung-Pil, Gupta, Mayuri, Oh, Myong In, Meek, Autumn, Doyle, Lisa, Villar, Laura, Brennecke, Anja, Liyanage, Imindu, Reed, Mark, Barden, Christopher, Weaver, Donald F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350920/
https://www.ncbi.nlm.nih.gov/pubmed/32704455
http://dx.doi.org/10.7717/peerj.9533
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author Wang, Zhiyu
Wang, Yanfei
Vilekar, Prachi
Yang, Seung-Pil
Gupta, Mayuri
Oh, Myong In
Meek, Autumn
Doyle, Lisa
Villar, Laura
Brennecke, Anja
Liyanage, Imindu
Reed, Mark
Barden, Christopher
Weaver, Donald F.
author_facet Wang, Zhiyu
Wang, Yanfei
Vilekar, Prachi
Yang, Seung-Pil
Gupta, Mayuri
Oh, Myong In
Meek, Autumn
Doyle, Lisa
Villar, Laura
Brennecke, Anja
Liyanage, Imindu
Reed, Mark
Barden, Christopher
Weaver, Donald F.
author_sort Wang, Zhiyu
collection PubMed
description The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia (“cytokine storm”). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19’s immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
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spelling pubmed-73509202020-07-22 Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide Wang, Zhiyu Wang, Yanfei Vilekar, Prachi Yang, Seung-Pil Gupta, Mayuri Oh, Myong In Meek, Autumn Doyle, Lisa Villar, Laura Brennecke, Anja Liyanage, Imindu Reed, Mark Barden, Christopher Weaver, Donald F. PeerJ Cell Biology The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia (“cytokine storm”). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19’s immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19. PeerJ Inc. 2020-07-07 /pmc/articles/PMC7350920/ /pubmed/32704455 http://dx.doi.org/10.7717/peerj.9533 Text en © 2020 Wang et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Cell Biology
Wang, Zhiyu
Wang, Yanfei
Vilekar, Prachi
Yang, Seung-Pil
Gupta, Mayuri
Oh, Myong In
Meek, Autumn
Doyle, Lisa
Villar, Laura
Brennecke, Anja
Liyanage, Imindu
Reed, Mark
Barden, Christopher
Weaver, Donald F.
Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title_full Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title_fullStr Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title_full_unstemmed Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title_short Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
title_sort small molecule therapeutics for covid-19: repurposing of inhaled furosemide
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350920/
https://www.ncbi.nlm.nih.gov/pubmed/32704455
http://dx.doi.org/10.7717/peerj.9533
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