High affinity modified ACE2 receptors protect from SARS-CoV-2 infection in hamsters

  1. Yusuke Higuchi
  2. Tatsuya Suzuki
  3. Takao Arimori
  4. Nariko Ikemura
  5. Emiko Mihara
  6. Yuhei Kirita
  7. Eriko Ohgitani
  8. Osam Mazda
  9. Daisuke Motooka
  10. Shota Nakamura
  11. Yusuke Sakai
  12. Yumi Itoh
  13. Fuminori Sugihara
  14. Yoshiharu Matsuura
  15. Satoaki Matoba
  16. Toru Okamoto
  17. Junichi Takagi
  18. Atsushi Hoshino

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor via receptor binding domain (RBD) to enter into the cell and inhibiting this interaction is a main approach to inhibit SARS-CoV-2 infection. We engineered ACE2 to enhance the affinity with directed evolution in 293T cells. Three cycles of random mutation and cell sorting achieved 100-fold higher affinity to RBD than wild-type ACE2. The extracellular domain of modified ACE2 fused to the human IgG1-Fc region had stable structure and neutralized SARS-CoV-2 without the emergence of mutational escape. Therapeutic administration protected hamsters from SARS-CoV-2 infection, decreasing lung virus titers and pathology. Engineering ACE2 decoy receptors with human cell-based directed evolution is a promising approach to develop a SARS-CoV-2 neutralizing drug that has affinity comparable to monoclonal antibodies yet displaying resistance to escape mutations of virus.

One Sentence Summary

Engineered ACE2 decoy receptor has a therapeutic potential against COVID-19 without viral escape mutation.

Article activity feed

  1. Version published to 10.1101/2020.09.16.299891v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.09.16.299891: (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

    Software and Algorithms
    SentencesResources
    S1 to S10 Tables S1 and S2 Movies S1 to S3 References (30-40) Materials and Methods:
    Methods
    suggested: None

    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: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 9 and 22. 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.
    • Thank you for including a protocol registration statement.

    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.

  3. Version published to 10.1101/2020.09.16.299891v1 on bioRxiv