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

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About: Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
Creator	Wang, Zhiyu Reed, Mark Barden, Christopher Brennecke, Anja Doyle, Lisa Gupta, Mayuri Liyanage, Imindu Meek, Autumn Oh, Myong Vilekar, Prachi Villar, Laura Wang, Yanfei Weaver, Donald Yang, Seung-Pil
Source	Medline; PMC
abstract	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.
has issue date	2020-07-07(xsd:dateTime)
bibo:doi	10.7717/peerj.9533
bibo:pmid	32704455
has license	cc-by
sha1sum (hex)	d08b5f00d3080aadae305bd7a549d82035c6bcdd
schema:url	https://doi.org/10.7717/peerj.9533
resource representing a document's title	Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
has PubMed Central identifier	PMC7350920
has PubMed identifier	32704455
schema:publication	PeerJ
resource representing a document's body	covid:d08b5f00d3080aadae305bd7a549d82035c6bcdd#body_text
is schema:about of	named entity 'morbidity' named entity 'NOVEL CORONAVIRUS' named entity 'SARS-COV-2' named entity 'morbidity' named entity 'viral infection' named entity 'Small molecule' named entity 'ALU' named entity 'mechanism of action' named entity 'IL-6' named entity 'Naples' named entity 'macrophages' named entity 'IL-6' named entity 'furosemide' named entity 'DMSO' named entity 'mechanism of action' named entity 'antibiotic-antimycotic' named entity 'anti-viral' named entity 'indoleamine' named entity 'drugbank' named entity 'human body' named entity 'PDB' named entity 'cytokine' named entity 'lysates' named entity 'nuclear factor' named entity 'immunoblotting' named entity 'conformer' named entity 'amino acids' named entity 'bloodstream' named entity 'TNF-a' named entity 'inducible nitric oxide synthase' named entity 'anti-inflammatory' named entity 'amino acid residues' named entity 'SARS-CoV' named entity 'alveolar macrophages' named entity 'structural components' named entity '1:250' named entity 'ligand' named entity 'envelope protein' named entity 'furosemide' named entity 'Chinese study' named entity 'ATP' named entity 'infection' named entity 'IL-6' named entity 'TNF-a' named entity 'binding site' named entity 'furosemide' named entity 'correlation' named entity '450 nm' named entity 'furosemide' named entity 'MOE' named entity 'phorbol 12-myristate 13-acetate' named entity 'pathogens' named entity 'Oxford Brookes University' named entity 'active sites' named entity 'chemiluminescence' named entity 'DMEM' named entity 'ligand' named entity 'TNF-a' named entity 'innate immunity' named entity 'global pandemic' named entity 'ligand' named entity 'signaling pathway' named entity 'DMSO' named entity 'dyspnea' named entity 'TLR4' named entity 'University of North Carolina' named entity 'phenotype' named entity 'crystallographic'

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