Unfractionated heparin inhibits live wild type SARS‐CoV‐2 cell infectivity at therapeutically relevant concentrations

Background and Purpose Currently, there are no licensed vaccines and limited antivirals for the treatment of COVID‐19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID‐19 patients. Additionally, in the United Kingdom, Brazil and Australia, nebulised unfrac...

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Veröffentlicht in:British journal of pharmacology Jg. 178; H. 3; S. 626 - 635
Hauptverfasser: Tree, Julia A., Turnbull, Jeremy E., Buttigieg, Karen R., Elmore, Michael J., Coombes, Naomi, Hogwood, John, Mycroft‐West, Courtney J., Lima, Marcelo A., Skidmore, Mark A., Karlsson, Richard, Chen, Yen‐Hsi, Yang, Zhang, Spalluto, Cosma Mirella, Staples, Karl J., Yates, Edwin A., Gray, Elaine, Singh, Dave, Wilkinson, Tom, Page, Clive P., Carroll, Miles W.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Blackwell Publishing Ltd 01.02.2021
John Wiley and Sons Inc
Schlagworte:
ACE2
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Anticoagulants
Antiviral activity
Antiviral agents
Antiviral Agents - pharmacology
Antiviral drugs
Chlorocebus aethiops
COVID-19
COVID-19 Drug Treatment
Heparin
Heparin - metabolism
Heparin - pharmacology
Heparin - therapeutic use
Heparin, Low-Molecular-Weight - pharmacology
Infectivity
LMWH
nebulised
Patients
Protein Binding - drug effects
Proteins
Research Paper
Research Papers
SARS-CoV-2 - growth & development
SARS‐CoV‐2
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - metabolism
Spike protein
Therapeutic applications
UFH
Viral Plaque Assay
Australia
COVID-19
heparin
nebulised
LMWH
SARS-CoV-2
UFH
ISSN:0007-1188, 1476-5381, 1476-5381
Online-Zugang:Volltext
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Zusammenfassung:Background and Purpose Currently, there are no licensed vaccines and limited antivirals for the treatment of COVID‐19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID‐19 patients. Additionally, in the United Kingdom, Brazil and Australia, nebulised unfractionated heparin (UFH) is being trialled in COVID‐19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild type SARS‐CoV‐2, in vitro, is needed. Experimental Approach Seven different heparin preparations including UFH and low MW heparins (LMWH) of porcine or bovine origin were screened for antiviral activity against live SARS‐CoV‐2 (Australia/VIC01/2020) using a plaque inhibition assay with Vero E6 cells. Interaction of heparin with spike protein RBD was studied using differential scanning fluorimetry and the inhibition of RBD binding to human ACE2 protein using elisa assays was examined. Key Results All the UFH preparations had potent antiviral effects, with IC50 values ranging between 25 and 41 μg·ml−1, whereas LMWHs were less inhibitory by ~150‐fold (IC50 range 3.4–7.8 mg·ml−1). Mechanistically, we observed that heparin binds and destabilizes the RBD protein and furthermore, we show heparin directly inhibits the binding of RBD to the human ACE2 protein receptor. Conclusion and Implications This comparison of clinically relevant heparins shows that UFH has significantly stronger SARS‐CoV‐2 antiviral activity compared to LMWHs. UFH acts to directly inhibit binding of spike protein to the human ACE2 protein receptor. Overall, the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID‐19.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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Julia A. Tree and Jeremy E. Turnbull are joint first authors.
ISSN:0007-1188
1476-5381
1476-5381
DOI:10.1111/bph.15304