The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases?

Med Hypotheses. 2020 Sep;142:109743. doi: 10.1016/j.mehy.2020.109743. Epub 2020 Apr 20.


Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the disease. At present, there is no specific antiviral drug or vaccine for COVID-19. The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1-S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk-benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.

Keywords: COVID-19; Factor Xa; Heparin; Host proteases; Low molecular weight heparin; SARS-CoV2.

MeSH terms

  • Betacoronavirus / drug effects*
  • COVID-19
  • COVID-19 Drug Treatment
  • Coronavirus Infections / blood
  • Coronavirus Infections / drug therapy*
  • Drug Administration Schedule
  • Factor Xa / metabolism
  • Heparin / pharmacology*
  • Heparin, Low-Molecular-Weight / pharmacology*
  • Humans
  • Models, Theoretical
  • Pandemics
  • Pneumonia, Viral / blood
  • Pneumonia, Viral / drug therapy*
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry


  • Heparin, Low-Molecular-Weight
  • Protease Inhibitors
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Heparin
  • Factor Xa