PRECLINICAL EVIDENCE FOR HEPARIN AS A SARS-CoV-2 ANTIVIRAL Beyond anticoagulation, there may be alternative beneficial mechanisms of action for heparin in patients with COVID-19 including direct SARS-CoV-2 antiviral activity. In a similar fashion to the related viruses severe acute respiratory coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), host cell fusion and entry are thought to be accomplished in SARS-CoV-2 infection via binding of the viral spike protein to host angiotensin-converting enzyme 2 (ACE2) receptors. Cofactors for this binding are incompletely understood for SARS-CoV-2; however, in vitro studies have demonstrated that cell surface heparan sulfate (the class of glycosaminoglycans of which heparin is composed) is essential for entry and infectivity with human coronavirus NL63 (23) and SARS-CoV (19). Heparan sulfate is thought to interact with the spike protein as an adhesion molecule coreceptor, which may be the first step in facilitating the interaction of SARS-CoV and the ACE2 receptor (23). It has recently been discovered that concordant with other coronaviruses, the SARS-CoV-2 spike protein also interacts with heparan sulfate, and with a higher affinity than either SARS-CoV or MERS-CoV spike proteins (17). In this study by Kim et al., the SARS-CoV-2 spike protein demonstrated extremely strong (and nearly irreversible) binding to heparin using surface plasmon resonance. Our developing understanding of the virology of SARS-CoV-2 suggests the biologic plausibility of heparin as an antiviral. Theoretically, heparin may bind the SARS-CoV-2 spike protein and function as a competitive inhibitor for viral entry, thus decreasing infectivity. Interestingly, shorter-length heparins, comparable to those found in therapeutic low-molecular weight heparin, did not appreciably bind the spike protein (17), suggesting that low-molecular weight formulations may be less likely to have direct antiviral activity through competitive spike protein binding. If clinical trials demonstrate benefit of unfractionated heparin therapy, its effect could be partially due to this theoretical antiviral activity, rather than solely due to its anticoagulant properties (38). As such, clinical trials with heparin should evaluate disease course and time to clearance of infection, as these outcomes would support direct antiviral activity. Despite the promise of this concept, no clinical data linking heparin therapy to meaningful antiviral outcomes exist. However, the use of heparin and other glycosaminoglycans as antiviral therapy has significant potential for future clinical applications. The utilization of heparan sulfate as a cofactor for viral entry appears to be conserved across the human coronaviruses as discussed, as well as the hepatitis C virus and herpesvirus family (8, 37). With a more in-depth understanding, this therapeutic strategy could be optimized for COVID-19, which may inform broad antiviral treatment with heparin and heparin-like drugs for future zoonotic coronaviruses and other viral pathogens.