An engineered decoy receptor for SARS-CoV-2 broadly binds protein S sequence variants

  1. Kui K. Chan
  2. Timothy J.C. Tan
  3. Krishna K. Narayanan
  4. Erik Procko

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Abstract

The spike S of SARS-CoV-2 recognizes ACE2 on the host cell membrane to initiate entry. Soluble decoy receptors, in which the ACE2 ectodomain is engineered to block S with high affinity, potently neutralize infection and, due to close similarity with the natural receptor, hold out the promise of being broadly active against virus variants without opportunity for escape. Here, we directly test this hypothesis. We find an engineered decoy receptor, sACE2 2 .v2.4, tightly binds S of SARS-associated viruses from humans and bats, despite the ACE2-binding surface being a region of high diversity. Saturation mutagenesis of the receptor-binding domain (RBD) followed by in vitro selection, with wild type ACE2 and the engineered decoy competing for binding sites, failed to find S mutants that discriminate in favor of the wild type receptor. Variant N501Y in the RBD, which has emerged in a rapidly spreading lineage (B.1.1.7) in England, enhances affinity for wild type ACE2 20-fold but remains tightly bound to engineered sACE22.v2.4. We conclude that resistance to engineered decoys will be rare and that decoys may be active against future outbreaks of SARS-associated betacoronaviruses.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.18.344622: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To measure competitive binding of wild type and engineered receptors, cells were instead incubated with 25 nM sACE22(WT)-IgG1 and 20 nM sACE22.v2.4-8h for 30 minutes at 4°C, washed twice, and stained with anti-human IgG-APC (clone HP6017, 1/250 dilution; BioLegend) and anti-HIS-FITC (chicken polyclonal, 1/100 dilution; Immunology Consultants Laboratory) secondary antibodies for 20 minutes at 4°C.
    anti-human IgG-APC
    suggested: None
    anti-HIS-FITC
    suggested: (Miltenyi Biotec Cat# 130-098-808, RRID:AB_2751026)
    Software and Algorithms
    SentencesResources
    Illumina sequencing data are deposited in NCBI’s Gene Expression Omnibus (GEO) under series accession number GSE159372.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)

    Results from OddPub: Thank you for sharing your data.

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04427501RecruitingA Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) i…
    NCT04427501RecruitingA Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) i…

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

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 11 and 13. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.10.18.344622 on bioRxiv