High activity of an affinity-matured ACE2 decoy against Omicron SARS-CoV-2 and pre-emergent coronaviruses

  1. Joshua J. Sims
  2. Sharon Lian
  3. Rosemary L. Meggersee
  4. Aradhana Kasimsetty
  5. James M. Wilson

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Abstract

The viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly its cell-binding spike protein gene, has undergone rapid evolution during the coronavirus disease 2019 (COVID-19) pandemic. Variants including Omicron BA.1 and Omicron BA.2 now seriously threaten the efficacy of therapeutic monoclonal antibodies and vaccines that target the spike protein. Viral evolution over a much longer timescale has generated a wide range of genetically distinct sarbecoviruses in animal populations, including the pandemic viruses SARS-CoV-2 and SARS-CoV-1. The genetic diversity and widespread zoonotic potential of this group complicates current attempts to develop drugs in preparation for the next sarbecovirus pandemic. Receptor-based decoy inhibitors can target a wide range of viral strains with a common receptor and may have intrinsic resistance to escape mutant generation and antigenic drift. We previously generated an affinity-matured decoy inhibitor based on the receptor target of the SARS-CoV-2 spike protein, angiotensin-converting enzyme 2 (ACE2), and deployed it in a recombinant adeno-associated virus vector (rAAV) for intranasal delivery and passive prophylaxis against COVID-19. Here, we demonstrate the exceptional binding and neutralizing potency of this ACE2 decoy against SARS-CoV-2 variants including Omicron BA.1 and Omicron BA.2. Tight decoy binding tracks with human ACE2 binding of viral spike receptor-binding domains across diverse clades of coronaviruses. Furthermore, in a coronavirus that cannot bind human ACE2, a variant that acquired human ACE2 binding was bound by the decoy with nanomolar affinity. Considering these results, we discuss a strategy of decoy-based treatment and passive protection to mitigate the ongoing COVID-19 pandemic and future airway virus threats.

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  1. Version published to 10.1371/journal.pone.0271359
  2. Version published to 10.1101/2022.01.17.476672v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2022.01.17.476672: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    We transfected the plasmid into Expi293 cells for expression.
    Expi293
    suggested: RRID:CVCL_D615)
    Recombinant DNA
    SentencesResources
    4.2 Recombinant protein production: To generate wt-ACE2-Fc for competitive binding assays, we cloned human ACE2 (1–615) fused to a C-terminal mouse IgG2a Fc into pcDNA3.1.
    pcDNA3.1
    suggested: RRID:Addgene_79663)
    The plasmid has a low-copy centromeric origin similar to that of pTCON2 (35).
    pTCON2
    suggested: None
    Software and Algorithms
    SentencesResources
    Using MEGA X (34), we aligned the amino acid sequences in ClustalW and constructed a phylogenic tree using maximum likelihood analysis.
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)
    We fitted the decoy concentration versus the decoy binding signal in GraphPad Prism using a three-parameter fit to the binding isotherm.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2022.01.17.476672v1 on bioRxiv