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Article

Enoxaparin and Pentosan Polysulfate Bind to the SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Inhibiting Vero Cell Infection

1
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, A-8010 Graz, Austria
2
Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, A-8010 Graz, Austria
3
Antagonis Biotherapeutics GmbH, Strasserhofweg 77a, A-8045 Graz, Austria
*
Author to whom correspondence should be addressed.
Academic Editors: Mauro Maniscalco and Pasquale Ambrosino
Biomedicines 2022, 10(1), 49; https://doi.org/10.3390/biomedicines10010049
Received: 30 November 2021 / Revised: 16 December 2021 / Accepted: 23 December 2021 / Published: 27 December 2021
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. View Full-Text
Keywords: SARS-CoV-2; COVID-19; Spike glycoprotein; heparan sulfate; dermatan sulfate; LMW heparin; pentosan polysulfate; PPS SARS-CoV-2; COVID-19; Spike glycoprotein; heparan sulfate; dermatan sulfate; LMW heparin; pentosan polysulfate; PPS
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MDPI and ACS Style

Ennemoser, M.; Rieger, J.; Muttenthaler, E.; Gerlza, T.; Zatloukal, K.; Kungl, A.J. Enoxaparin and Pentosan Polysulfate Bind to the SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Inhibiting Vero Cell Infection. Biomedicines 2022, 10, 49. https://doi.org/10.3390/biomedicines10010049

AMA Style

Ennemoser M, Rieger J, Muttenthaler E, Gerlza T, Zatloukal K, Kungl AJ. Enoxaparin and Pentosan Polysulfate Bind to the SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Inhibiting Vero Cell Infection. Biomedicines. 2022; 10(1):49. https://doi.org/10.3390/biomedicines10010049

Chicago/Turabian Style

Ennemoser, Maria, Julia Rieger, Eva Muttenthaler, Tanja Gerlza, Kurt Zatloukal, and Andreas J. Kungl. 2022. "Enoxaparin and Pentosan Polysulfate Bind to the SARS-CoV-2 Spike Protein and Human ACE2 Receptor, Inhibiting Vero Cell Infection" Biomedicines 10, no. 1: 49. https://doi.org/10.3390/biomedicines10010049

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