Clinical grade ACE2 as a universal agent to block SARS‐CoV‐2 variants

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Abstract

The recent emergence of multiple SARS‐CoV‐2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS‐CoV‐2 variants. Here, we report that all SARS‐CoV‐2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by all current VOC strains with markedly enhanced potency when compared to reference SARS‐CoV‐2 isolates. Effective inhibition of infections with SARS‐CoV‐2 variants was validated and confirmed in two independent laboratories. These data show that SARS‐CoV‐2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan‐SARS‐CoV‐2 therapeutic.

Abstract

Recombinant human ACE2 is reported as a “universal” therapeutic approach, exhibiting strong potency and efficacy for the inhibition of SARS‐CoV‐2 infection, especially towards current variants of concern.

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Most cited references 61

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

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

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

Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett … (2020)

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

Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)

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

Gerald Wirnsberger:

ORCID: https://orcid.org/0000-0001-7035-7038

gwi@invios.com

Josef M Penninger:

ORCID: https://orcid.org/0000-0002-8194-3777

josef.penninger@ubc.ca

Journal

Journal ID (nlm-ta): EMBO Mol Med

Journal ID (iso-abbrev): EMBO Mol Med

Journal ID (doi): 10.1002/(ISSN)1757-4684

Journal ID (publisher-id): EMMM

Journal ID (hwp): embomm

Title: EMBO Molecular Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1757-4676

ISSN (Electronic): 1757-4684

Publication date (Electronic): 04 July 2022

Publication date PMC-release: 04 July 2022

Electronic Location Identifier: e15230

Affiliations

[ ¹ ] Unit of Clinical Microbiology Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

[ ² ] NIAID Integrated Research Facility at Fort Detrick (IRF‐Frederick) Frederick Maryland USA

[ ³ ] Institute for Molecular Modeling and Simulation University of Natural Resources and Life Sciences (BOKU) Vienna Austria

[ ⁴ ] Clinical Research Monitoring Program Directorate Frederick National Laboratory for Cancer Research Frederick Maryland USA

[ ⁵ ] NBS‐C BioScience & Consulting GmbH Vienna Austria

[ ⁶ ] invIOs Vienna Austria

[ ⁷ ] Center for Infectious Medicine Department of Medicine Huddinge Karolinska Institutet Stockholm Sweden

[ ⁸ ] Department of Clinical Sciences Karolinska Institute Danderyd Hospital Stockholm Sweden

[ ⁹ ] Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria

[ ¹⁰ ] Vienna BioCenter PhD Program, Doctoral School of the University at Vienna and Medical University of Vienna Vienna Austria

[ ¹¹ ] Department of Medicine 1, Laboratory of Infection Biology Medical University of Vienna Vienna Austria

[ ¹² ] Pluripotency for Organ Regeneration Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST) Barcelona Spain

[ ¹³ ] Catalan Institution for Research and Advanced Studies (ICREA) Barcelona Spain

[ ¹⁴ ] Department of Medical Genetics, Life Sciences Institute University of British Columbia Vancouver Canada

[ ¹⁵ ] Institute of Biochemistry, Department of Chemistry University of Natural resources and Life, Sciences (BOKU) Vienna Austria

[ ¹⁶ ] Chemopreventive Agent Development Research Group, Division of Cancer Prevention National Cancer Institute, National Institutes of Health Bethesda Maryland USA

Author notes

[*] [* ] Corresponding author. Tel: +43 1 8656577300; E‐mail: gwi@ 123456invios.com

Corresponding author. Tel: +1 604 8270347; E‐mail: josef.penninger@ 123456ubc.ca

Author information

Vanessa Monteil https://orcid.org/0000-0002-2652-5695

Benedict Braunsfeld https://orcid.org/0000-0002-0286-8239

Stephanie Devignot https://orcid.org/0000-0002-0618-5611

Jonas Klingström https://orcid.org/0000-0001-9076-1441

Stefan Mereiter https://orcid.org/0000-0002-4832-3090

Sylvia Knapp https://orcid.org/0000-0001-9016-5244

Agnes Bugajska‐Schretter https://orcid.org/0000-0002-2096-5833

Alexander Dohnal https://orcid.org/0000-0002-5844-7329

Astrid Hagelkruys https://orcid.org/0000-0003-3015-4038

Nuria Montserrat https://orcid.org/0000-0002-1603-1755

Ivona Kozieradzki https://orcid.org/0000-0001-8189-3346

Omar Hasan Ali https://orcid.org/0000-0001-5185-7520

Johannes Stadlmann https://orcid.org/0000-0001-5693-6690

Michael R Holbrook https://orcid.org/0000-0002-0824-2667

Chris Oostenbrink https://orcid.org/0000-0002-4232-2556

Robert H Shoemaker https://orcid.org/0000-0003-3608-1714

Ali Mirazimi https://orcid.org/0000-0003-2371-6055

Gerald Wirnsberger https://orcid.org/0000-0001-7035-7038

Josef M Penninger https://orcid.org/0000-0002-8194-3777

Article

Publisher ID: EMMM202115230

DOI: 10.15252/emmm.202115230

PMC ID: 9350269

PubMed ID: 35781796

SO-VID: 9e1f45a5-4bb0-4b48-b53a-addec9470368

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 03 June 2022

Date received : 30 September 2021

Date accepted : 03 June 2022

Page count

Figures: 6, Tables: 0, Pages: 14, Words: 11446

Funding

Funded by: Austrian Science Fund (FWF) , doi 10.13039/501100002428;

Award ID: Z 271‐B19

Funded by: Canada 150 Chair

Award ID: F18‐01336

Funded by: Center for Strategic Scientific Initiatives, National Cancer Institute (CSSI, NCI) , doi 10.13039/100008637;

Award ID: 75N91019D00024

Award ID: 75N91019F00130

Funded by: Gouvernement du Canada ¦ Canadian Institutes of Health Research (IRSC) , doi 10.13039/501100000024;

Award ID: F20‐02343

Award ID: F20‐02015

Funded by: Innovative Medicines Initiative (IMI) , doi 10.13039/501100010767;

Award ID: 101005026

Funded by: T. von Zastrow foundation Swiss National Science Foundation (SNSF)

Funded by: Swiss National Science Foundation (SNSF)

Award ID: P400PM_194473

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details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:04.08.2022

ScienceOpen disciplines: Molecular medicine

Keywords: covid‐19,treatment,clinical trial,vaccine,microbiology, virology & host pathogen interaction

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ScienceOpen disciplines: Molecular medicine

Keywords: covid‐19, treatment, clinical trial, vaccine, microbiology, virology & host pathogen interaction

Clinical grade ACE2 as a universal agent to block SARS‐CoV‐2 variants

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Abstract

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Novel Coronavirus Disease COVID-19

Most cited references 61

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

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

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

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