De novo design of ACE2 protein decoys to neutralize SARS-CoV-2

  1. Thomas W. Linsky
  2. Renan Vergara
  3. Nuria Codina
  4. Jorgen W. Nelson
  5. Matthew J. Walker
  6. Wen Su
  7. Tien-Ying Hsiang
  8. Katharina Esser-Nobis
  9. Kevin Yu
  10. Yixuan J. Hou
  11. Tanu Priya
  12. Masaya Mitsumoto
  13. Avery Pong
  14. Uland Y. Lau
  15. Marsha L. Mason
  16. Jerry Chen
  17. Alex Chen
  18. Tania Berrocal
  19. Hong Peng
  20. Nicole S. Clairmont
  21. Javier Castellanos
  22. Yu-Ru Lin
  23. Anna Josephson-Day
  24. Ralph Baric
  25. Carl D. Walkey
  26. Ryan Swanson
  27. Michael Gale
  28. Luis M. Blancas-Mejia
  29. Hui-Ling Yen
  30. Daniel-Adriano Silva

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Abstract

There is an urgent need for the ability to rapidly develop effective countermeasures for emerging biological threats, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a generalized computational design strategy to rapidly engineer de novo proteins that precisely recapitulate the protein surface targeted by biological agents, like viruses, to gain entry into cells. The designed proteins act as decoys that block cellular entry and aim to be resilient to viral mutational escape. Using our novel platform, in less than ten weeks, we engineered, validated, and optimized de novo protein decoys of human angiotensin-converting enzyme 2 (hACE2), the membrane-associated protein that SARS-CoV-2 exploits to infect cells. Our optimized designs are hyperstable de novo proteins (∼18-37 kDa), have high affinity for the SARS-CoV-2 receptor binding domain (RBD) and can potently inhibit the virus infection and replication in vitro. Future refinements to our strategy can enable the rapid development of other therapeutic de novo protein decoys, not limited to neutralizing viruses, but to combat any agent that explicitly interacts with cell surface proteins to cause disease.

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    SciScore for 10.1101/2020.08.03.231340: (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

    No key resources detected.

    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 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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.08.03.231340 on bioRxiv