PMID- 33125711
OWN - NLM
STAT- MEDLINE
DCOM- 20210125
LR  - 20221207
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 178
IP  - 3
DP  - 2021 Feb
TI  - Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at 
      therapeutically relevant concentrations.
PG  - 626-635
LID - 10.1111/bph.15304 [doi]
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 IC(50) values ranging between 25 
      and 41 mug.ml(-1) , whereas LMWHs were less inhibitory by ~150-fold (IC(50) 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.
CI  - (c) 2020 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Tree, Julia A
AU  - Tree JA
AD  - National Infection Service, Public Health England, Porton Down, Salisbury, UK.
FAU - Turnbull, Jeremy E
AU  - Turnbull JE
AD  - Department of Biochemistry and Systems Biology, Institute of Systems, Molecular & 
      Integrative Biology, University of Liverpool, Liverpool, UK.
AD  - Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Buttigieg, Karen R
AU  - Buttigieg KR
AD  - National Infection Service, Public Health England, Porton Down, Salisbury, UK.
FAU - Elmore, Michael J
AU  - Elmore MJ
AD  - National Infection Service, Public Health England, Porton Down, Salisbury, UK.
FAU - Coombes, Naomi
AU  - Coombes N
AD  - National Infection Service, Public Health England, Porton Down, Salisbury, UK.
FAU - Hogwood, John
AU  - Hogwood J
AD  - Haemostasis Section, Biotherapeutics, National Institute for Biological Standards 
      and Control (NIBSC), Potters Bar, UK.
FAU - Mycroft-West, Courtney J
AU  - Mycroft-West CJ
AD  - Molecular & Structural Biosciences, School of Life Sciences, Keele University, 
      Newcastle-Under-Lyme, UK.
FAU - Lima, Marcelo A
AU  - Lima MA
AD  - Molecular & Structural Biosciences, School of Life Sciences, Keele University, 
      Newcastle-Under-Lyme, UK.
FAU - Skidmore, Mark A
AU  - Skidmore MA
AD  - Molecular & Structural Biosciences, School of Life Sciences, Keele University, 
      Newcastle-Under-Lyme, UK.
FAU - Karlsson, Richard
AU  - Karlsson R
AD  - Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Chen, Yen-Hsi
AU  - Chen YH
AD  - Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Yang, Zhang
AU  - Yang Z
AD  - Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Spalluto, Cosma Mirella
AU  - Spalluto CM
AD  - Department of Respiratory Medicine, University of Southampton, Southampton, UK.
FAU - Staples, Karl J
AU  - Staples KJ
AD  - Department of Respiratory Medicine, University of Southampton, Southampton, UK.
FAU - Yates, Edwin A
AU  - Yates EA
AD  - Department of Biochemistry and Systems Biology, Institute of Systems, Molecular & 
      Integrative Biology, University of Liverpool, Liverpool, UK.
FAU - Gray, Elaine
AU  - Gray E
AD  - Haemostasis Section, Biotherapeutics, National Institute for Biological Standards 
      and Control (NIBSC), Potters Bar, UK.
AD  - Sackler Institute of Pulmonary Pharmacology, King's College London, London, UK.
FAU - Singh, Dave
AU  - Singh D
AD  - Medicines Evaluation Unit, University of Manchester, Manchester University 
      Hospital NHS Foundation Trust, Manchester, UK.
FAU - Wilkinson, Tom
AU  - Wilkinson T
AD  - Department of Respiratory Medicine, University of Southampton, Southampton, UK.
FAU - Page, Clive P
AU  - Page CP
AD  - Sackler Institute of Pulmonary Pharmacology, King's College London, London, UK.
FAU - Carroll, Miles W
AU  - Carroll MW
AD  - National Infection Service, Public Health England, Porton Down, Salisbury, UK.
AD  - Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, Oxford 
      University, Oxford, UK.
LA  - eng
GR  - G0700852/MRC_/Medical Research Council/United Kingdom
GR  - University of Liverpool/International
GR  - University of Keele/International
GR  - Public Health England/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201214
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Antiviral Agents)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Spike Glycoprotein, Coronavirus)
RN  - 0 (spike protein, SARS-CoV-2)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
SB  - IM
MH  - Angiotensin-Converting Enzyme 2/metabolism
MH  - Animals
MH  - Antiviral Agents/pharmacology
MH  - Chlorocebus aethiops
MH  - Heparin/metabolism/*pharmacology/therapeutic use
MH  - Heparin, Low-Molecular-Weight/pharmacology
MH  - Protein Binding/drug effects
MH  - SARS-CoV-2/*growth & development
MH  - Spike Glycoprotein, Coronavirus/metabolism
MH  - Viral Plaque Assay
MH  - COVID-19 Drug Treatment
PMC - PMC9328389
OTO - NOTNLM
OT  - COVID-19
OT  - LMWH
OT  - SARS-CoV-2
OT  - UFH
OT  - heparin
OT  - nebulised
COIS- The authors have no conflicts of interest to declare.
EDAT- 2020/10/31 06:00
MHDA- 2021/01/26 06:00
PMCR- 2020/12/14
CRDT- 2020/10/30 17:15
PHST- 2020/07/13 00:00 [received]
PHST- 2020/10/08 00:00 [revised]
PHST- 2020/10/18 00:00 [accepted]
PHST- 2020/10/31 06:00 [pubmed]
PHST- 2021/01/26 06:00 [medline]
PHST- 2020/10/30 17:15 [entrez]
PHST- 2020/12/14 00:00 [pmc-release]
AID - BPH15304 [pii]
AID - 10.1111/bph.15304 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2021 Feb;178(3):626-635. doi: 10.1111/bph.15304. Epub 2020 Dec 
      14.