Abstract

As with many other pathogens, SARS-CoV-2 cell infection is strongly dependent on the interaction of the virus-surface Spike protein with the glycosaminoglycans of target cells. The SARS-CoV-2 Spike glycoprotein was previously shown to interact with cell-surface-exposed heparan sulfate and heparin in vitro. With the aim of using Enoxaparin as a treatment for COVID-19 patients and as prophylaxis to prevent interpersonal viral transmission, we investigated GAG binding to the Spike full-length protein, as well as to its receptor binding domain (RBD) in solution by isothermal fluorescence titration. We found that Enoxaparin bound to both protein variants with similar affinities, compared to the natural GAG ligand heparan sulfate (with Kd-values in the range of 600–680 nM). Using size-defined Enoxaparin fragments, we discovered the optimum binding for dp6 or dp8 for the full-length Spike protein, whereas the RBD did not exhibit a significant chain-length-dependent affinity for heparin oligosaccharides. The soluble ACE2 receptor was found to interact with unfractionated GAGs in the low µM Kd range, but with size-defined heparins with clearly sub-µM Kd-values. Interestingly, the structural heparin analogue, pentosan polysulfate (PPS), exhibited high binding affinities to both Spike variants as well as to the ACE2 receptor. In viral infection experiments, Enoxaparin and PPS both showed a strong inhibition of infection in a concentration range of 50–500 µg/mL. Both compounds were found to retain their inhibitory effects at 500 µg/mL in a natural biomatrix-like human sputum. Our data suggest the early topical treatment of SARS-CoV-2 infections with inhaled Enoxaparin; some clinical studies in this direction are already ongoing, and they further imply an oral or nasal prophylactic inactivation of the virus by Enoxaparin or PPS for the prevention of inter-personal viral transmission.

Highlights

  • IntroductionAs of November 2021, the ongoing COVID-19 pandemic has claimed over 5.17 million lives and severely affected our social and economic lives

  • Spike Full-length Spike protein (FL) was found to bind to Enoxaparin (Kd 604.3 ± 67.4 nM) slightly better than heparan sulfate (HS)

  • We presented evidence that enoxaparin interacts with the spike protein of Severe acute respiratory syndrome (SARS)-CoV-2 virus, thereby preventing viral infection/propagation in target cells

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Summary

Introduction

As of November 2021, the ongoing COVID-19 pandemic has claimed over 5.17 million lives and severely affected our social and economic lives. Severe acute respiratory syndrome (SARS) is caused by a considerably new beta coronavirus, globally known as severe acute respiratory syndrome virus 2 (SARS-CoV-2) [1,2], and it has caused a variety of clinical morbidities and high mortality rates [3]. Clinical manifestations are versatile, ranging from asymptomatic disease progression to flu-like symptoms including fever, cough, dyspnea and fatigue, to even multiorgan failure and rapid death [4].

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