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      Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties†

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          Abstract

          SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19.

          Abstract

          SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host proteins for viral entry into human lung cells and is blocked by otamixaban in combination with a covalent protease inhibitor.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            SciPy 1.0: fundamental algorithms for scientific computing in Python

            SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.
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              VMD: Visual molecular dynamics

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                Author and article information

                Journal
                Chem Sci
                Chem Sci
                SC
                CSHCBM
                Chemical Science
                The Royal Society of Chemistry
                2041-6520
                2041-6539
                26 August 2021
                6 October 2021
                26 August 2021
                : 12
                : 38
                : 12600-12609
                Affiliations
                [a] Department of Mathematics and Computer Science, Freie Universität Berlin Berlin Germany frank.noe@ 123456fu-berlin.de
                [b] Department of Physics, Freie Universität Berlin Berlin Germany
                [c] Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research Göttingen Germany
                [d] National Center for Advancing Translational Sciences, National Institutes of Health Rockville MD USA
                [e] Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR) Hannover Germany
                [f] Institute of Pathology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Hannover Germany
                [g] Faculty of Biology and Psychology, University Göttingen Göttingen Germany
                [h] Department of Chemistry, Rice University Houston TX USA
                Author notes
                [‡]

                Equal contribution.

                Author information
                https://orcid.org/0000-0002-0073-9353
                https://orcid.org/0000-0002-6160-8701
                https://orcid.org/0000-0002-5493-6205
                https://orcid.org/0000-0003-4603-7696
                https://orcid.org/0000-0003-4169-9324
                Article
                d1sc01494c
                10.1039/d1sc01494c
                8494051
                34703545
                fa0f94c2-792b-4030-b585-87e8bd2e05b8
                This journal is © The Royal Society of Chemistry
                History
                : 15 March 2021
                : 20 July 2021
                Page count
                Pages: 10
                Funding
                Funded by: European Commission, doi 10.13039/501100000780;
                Award ID: ERC CoG 772230 “ScaleCell”
                Award ID: ERC Consolidator Grant 771883 “XHale”
                Funded by: Berlin Mathematics Research Center MATH+, doi 10.13039/501100019239;
                Award ID: AA1-6
                Award ID: AA1-10
                Funded by: Deutsche Forschungsgemeinschaft, doi 10.13039/501100001659;
                Award ID: PO 716/11-1
                Award ID: PO 716/14-1
                Award ID: SFB 1114, Project C03
                Award ID: SFB/TRR 186, Project A12
                Funded by: Bundesministerium für Bildung und Forschung, doi 10.13039/501100002347;
                Award ID: ANI-CoV 01KI2074A
                Award ID: BIFOLD
                Award ID: COVIM 01KX2021
                Award ID: RAPID 01KI1723D, 01KI2006D
                Award ID: RENACO 01KI20328A
                Award ID: SARS_S1S2 01KI20396
                Funded by: H2020 Marie Skłodowska-Curie Actions, doi 10.13039/100010665;
                Award ID: 897414
                Funded by: National Center for Advancing Translational Sciences, doi 10.13039/100006108;
                Award ID: Unassigned
                Funded by: Fraunhofer-Gesellschaft, doi 10.13039/501100003185;
                Award ID: Anti-Corona 840260 DRECOR
                Categories
                Chemistry
                Custom metadata
                Paginated Article

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