Multivalent designed proteins protect against SARS-CoV-2 variants of concern

  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. Bastain Vögeli
  23. Antje Krüger-Gericke
  24. Laura A. VanBlargan
  25. Rita E. Chen
  26. Baoling Ying
  27. Adam L. Bailey
  28. Natasha M. Kafai
  29. Scott Boyken
  30. Ajasja Ljubetič
  31. Natasha Edman
  32. George Ueda
  33. Cameron Chow
  34. Amin Addetia
  35. Nuttada Panpradist
  36. Michael Gale
  37. Benjamin S. Freedman
  38. Barry R. Lutz
  39. Jesse D. Bloom
  40. Hannele Ruohola-Baker
  41. Sean P. J. Whelan
  42. Lance Stewart
  43. Michael S. Diamond
  44. David Veesler
  45. Michael C. Jewett
  46. David Baker
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Abstract

Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC50values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness.

One-Sentence Summary

We designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.

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