Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice

  1. Andrew C. Hunt
  2. James Brett Case
  3. Young-Jun Park
  4. Longxing Cao
  5. Kejia Wu
  6. Alexandra C. Walls
  7. Zhuoming Liu
  8. John E. Bowen
  9. Hsien-Wei Yeh
  10. Shally Saini
  11. Louisa Helms
  12. Yan Ting Zhao
  13. Tien-Ying Hsiang
  14. Tyler N. Starr
  15. Inna Goreshnik
  16. Lisa Kozodoy
  17. Lauren Carter
  18. Rashmi Ravichandran
  19. Lydia B. Green
  20. Wadim L. Matochko
  21. Christy A. Thomson
  22. Bastian Vögeli
  23. Antje Krüger
  24. Laura A. VanBlargan
  25. Rita E. Chen
  26. Baoling Ying
  27. Adam L. Bailey
  28. Natasha M. Kafai
  29. Scott E. Boyken
  30. Ajasja Ljubetič
  31. Natasha Edman
  32. George Ueda
  33. Cameron M. Chow
  34. Max Johnson
  35. Amin Addetia
  36. Mary-Jane Navarro
  37. Nuttada Panpradist
  38. Michael Gale
  39. Benjamin S. Freedman
  40. Jesse D. Bloom
  41. Hannele Ruohola-Baker
  42. Sean P. J. Whelan
  43. Lance Stewart
  44. Michael S. Diamond
  45. David Veesler
  46. Michael C. Jewett
  47. David Baker

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Abstract

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.

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  1. Version published to 10.1126/scitranslmed.abn1252
  2. ScreenIT

    SciScore for 10.1101/2021.07.07.451375: (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.

    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.
    • 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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  3. Version published to 10.1101/2021.07.07.451375v1 on bioRxiv