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      An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

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          Abstract

          The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG 1F C fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.

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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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            Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

            Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260
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              Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

              Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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                Author and article information

                Contributors
                Shiho.tanaka@immunitybio.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                17 June 2021
                17 June 2021
                2021
                : 11
                : 12740
                Affiliations
                [1 ]ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA 90232 USA
                [2 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Center for Inborn Errors of Immunity, , Icahn School of Medicine at Mount Sinai, ; 1 Gustave Lane, Levy Place, New York, NY 10029-5674 USA
                [3 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, ; 1 Gustave Lane, Levy Place, New York, NY 10029-5674 USA
                [4 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Microbiology, , Icahn School of Medicine at Mount Sinai, ; 1 Gustave Lane, Levy Place, New York, NY 10029-5674 USA
                [5 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Pediatrics, , Icahn School of Medicine at Mount Sinai, ; 1 Gustave Lane, Levy Place, New York, NY 10029-5674 USA
                [6 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, ; 1 Gustave Lane, Levy Place, New York, NY 10029-5674 USA
                Article
                91809
                10.1038/s41598-021-91809-9
                8211782
                33414495
                57c2aeb1-e835-44a1-9d71-5ca16f782f00
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 March 2021
                : 26 May 2021
                Categories
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                © The Author(s) 2021

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                biophysics,drug discovery
                Uncategorized
                biophysics, drug discovery

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