Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations
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Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations. / 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.
In: British Journal of Pharmacology, Vol. 178, No. 3, 2021, p. 626-635.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations
AU - Tree, Julia A.
AU - Turnbull, Jeremy E.
AU - Buttigieg, Karen R.
AU - Elmore, Michael J.
AU - Coombes, Naomi
AU - Hogwood, John
AU - Mycroft-West, Courtney J.
AU - Lima, Marcelo A.
AU - Skidmore, Mark A.
AU - Karlsson, Richard
AU - Chen, Yen Hsi
AU - Yang, Zhang
AU - Spalluto, Cosma Mirella
AU - Staples, Karl J.
AU - Yates, Edwin A.
AU - Gray, Elaine
AU - Singh, Dave
AU - Wilkinson, Tom
AU - Page, Clive P.
AU - Carroll, Miles W.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - COVID-19
KW - heparin
KW - LMWH
KW - nebulised
KW - SARS-CoV-2
KW - UFH
U2 - 10.1111/bph.15304
DO - 10.1111/bph.15304
M3 - Journal article
C2 - 33125711
AN - SCOPUS:85096138013
VL - 178
SP - 626
EP - 635
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 3
ER -
ID: 256264301