The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE...
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| Published in: | Frontiers in pharmacology Vol. 12; p. 660490 |
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| Language: | English |
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06.08.2021
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| ISSN: | 1663-9812, 1663-9812 |
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| Abstract | The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection. |
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| AbstractList | The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection. |
| Author | Turnbull, Jeremy E. Pagani, Isabel Vicenzi, Elisa Richardson, Alan Hill, Harriet J. Davies, Scott P. Skidmore, Mark A. Guimond, Scott E. Mycroft-West, Courtney J. Khanim, Farhat L. Karlsson, Richard Bagdonaite, Ieva Chen, Yen-Hsi Yang, Zhang Stamataki, Zania De Lima, Marcelo Andrade |
| AuthorAffiliation | 6 School of Biomedical Sciences, Institute for Clinical Sciences, University of Birmingham, Birmingham , United Kingdom 5 Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool , United Kingdom 2 Molecular and Structural Bioscience, School of Life Sciences, Keele University, Staffordshire , United Kingdom 4 Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen , Denmark 3 Viral Pathogenesis and Biosafety Unit, San Raffaele Scientific Institute Via Olgettina, Milano , Italy 1 Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham , United Kingdom 7 School of Pharmacy and Bioengineering, Keele University, Staffordshire , United Kingdom |
| AuthorAffiliation_xml | – name: 6 School of Biomedical Sciences, Institute for Clinical Sciences, University of Birmingham, Birmingham , United Kingdom – name: 4 Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen , Denmark – name: 2 Molecular and Structural Bioscience, School of Life Sciences, Keele University, Staffordshire , United Kingdom – name: 5 Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool , United Kingdom – name: 1 Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham , United Kingdom – name: 7 School of Pharmacy and Bioengineering, Keele University, Staffordshire , United Kingdom – name: 3 Viral Pathogenesis and Biosafety Unit, San Raffaele Scientific Institute Via Olgettina, Milano , Italy |
| Author_xml | – sequence: 1 givenname: Scott P. surname: Davies fullname: Davies, Scott P. – sequence: 2 givenname: Courtney J. surname: Mycroft-West fullname: Mycroft-West, Courtney J. – sequence: 3 givenname: Isabel surname: Pagani fullname: Pagani, Isabel – sequence: 4 givenname: Harriet J. surname: Hill fullname: Hill, Harriet J. – sequence: 5 givenname: Yen-Hsi surname: Chen fullname: Chen, Yen-Hsi – sequence: 6 givenname: Richard surname: Karlsson fullname: Karlsson, Richard – sequence: 7 givenname: Ieva surname: Bagdonaite fullname: Bagdonaite, Ieva – sequence: 8 givenname: Scott E. surname: Guimond fullname: Guimond, Scott E. – sequence: 9 givenname: Zania surname: Stamataki fullname: Stamataki, Zania – sequence: 10 givenname: Marcelo Andrade surname: De Lima fullname: De Lima, Marcelo Andrade – sequence: 11 givenname: Jeremy E. surname: Turnbull fullname: Turnbull, Jeremy E. – sequence: 12 givenname: Zhang surname: Yang fullname: Yang, Zhang – sequence: 13 givenname: Elisa surname: Vicenzi fullname: Vicenzi, Elisa – sequence: 14 givenname: Mark A. surname: Skidmore fullname: Skidmore, Mark A. – sequence: 15 givenname: Farhat L. surname: Khanim fullname: Khanim, Farhat L. – sequence: 16 givenname: Alan surname: Richardson fullname: Richardson, Alan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34421587$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2021 Davies, Mycroft-West, Pagani, Hill, Chen, Karlsson, Bagdonaite, Guimond, Stamataki, De Lima, Turnbull, Yang, Vicenzi, Skidmore, Khanim and Richardson. Copyright © 2021 Davies, Mycroft-West, Pagani, Hill, Chen, Karlsson, Bagdonaite, Guimond, Stamataki, De Lima, Turnbull, Yang, Vicenzi, Skidmore, Khanim and Richardson. 2021 Davies, Mycroft-West, Pagani, Hill, Chen, Karlsson, Bagdonaite, Guimond, Stamataki, De Lima, Turnbull, Yang, Vicenzi, Skidmore, Khanim and Richardson |
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| Keywords | COVID-19 ACE2 SARS-CoV-2 fenofibrate fibrate |
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| License | Copyright © 2021 Davies, Mycroft-West, Pagani, Hill, Chen, Karlsson, Bagdonaite, Guimond, Stamataki, De Lima, Turnbull, Yang, Vicenzi, Skidmore, Khanim and Richardson. 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. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors share last authorship Edited by:Lei Xi, Virginia Commonwealth University, United States Reviewed by:Kirill Gorshkov, National Center for Advancing Translational Sciences (NCATS), United States Maria Cristina Albertini, University of Urbino Carlo Bo, Italy This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology |
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| Title | The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models |
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