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

PeerJ

article

Zhiyu Wang¹  Yanfei Wang¹  Prachi Vilekar¹  Seung-Pil Yang¹  Mayuri Gupta¹  Myong In Oh¹  Autumn Meek¹  Lisa Doyle¹  Laura Villar¹  Anja Brennecke¹  Imindu Liyanage¹  Mark Reed¹  Christopher Barden¹  Donald F. Weaver¹ 

[1] Krembil Research Institute, University Health Network;Faculty of Pharmacy, University of Toronto;Faculty of Medicine, University of Toronto;Department of Pharmacology and Toxicology, University of Toronto

关键词: Furosemide;    COVID-19;    Cytokine storm;    Hypercytokinemia;    Coronavirus;    Anti-inflammatory;   

DOI  :  10.7717/peerj.9533

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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.

【 授权许可】

CC BY