Enoxaparin's potential mechanisms against SARS-CoV-2.

Abstract

Since the coronavirus disease 2019 (COVID-19) pandemic emerged, the number of infected people has surged. As of late September 2022, about 614 million cases of COVID-19 have been confirmed and the death toll has exceeded 6.52 million1. Heparin and low-molecular-weight heparin (LMWH) are the anticoagulants of choice in the treatment of moderate to severe COVID-19, according to the most recent National Institutes of Health COVID-19 treatment guidelines2. Furthermore, heparin and LMWH have anti-inflammatory properties due to their ability to inhibit inflammatory cytokines, particularly interleukin-63. The antiviral activity of heparin against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in the literature, but this unique feature of enoxaparin is still unknown4. Recent evidence suggests that enoxaparin has potential mechanisms of action against SARS-CoV-2, giving the drug an important role in the treatment of COVID-19. Clausen et al.5 demonstrated that heparan sulphate (HS) plays a pivotal role in the pathogenesis of SARS-CoV-2, in which the SARS-CoV-2 spike protein can bind to both cellular HS and human angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain, and that it also augments the attachment of the SARS-CoV-2 spike protein and ACE2. One of the key antiviral mechanisms of enoxaparin comes from its ability to bind to the site of HS on the SARS-CoV-2 spike protein and ACE2, which inhibits the virus-cell entry and consequent infection6. The most recently proposed mechanism is that enoxaparin can significantly boost the alpha-1-antitrypsin inhibition of transmembrane serine protease 2, which cleaves the SARS-CoV-2 spike protein at the S1/S2 site for virus–cell entry7. This mechanism is clinically relevant and more likely to be resistant to the SARS-CoV-2 mutations. Furthermore, both enoxaparin and alpha-1-antitrypsin have anti-inflammatory properties in COVID-197. Finally, it has been revealed that heparanase plays an important role in the SARS-CoV-2 infection and has a significant relationship with the severity of COVID-19. Data suggest that LMWH may potentially inhibit heparanase and prevent SARS-CoV-2 cell entry and spread. Interestingly, heparanase has a detrimental effect on endothelial damage and causes vascular leakage and inflammation, which could be blocked by LMWH8. This document briefly reviews the suggested antiviral mechanisms of enoxaparin and can be used as the basis for further investigations. Ethical approval None. Source of funding None. Author contribution B.A.: conceptualization, writing—original draft. T.E.M.: writing—review and editing, supervision. Conflicts of interest disclosure The authors declare no conflicts of interest. Research registration unique identifying number (UIN) None. Guarantor All authors. Competing interests Sponsorships or competing interests that may be relevant to the content are disclosed at the end of this article. Data statement Our manuscript does not have new data to share. No funding was received for this correspondence item.