Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice-Reference-Cited by-同舟云学术

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

Published:2022-05-25 Issue:646 Volume:14 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Hunt Andrew C.¹²^ORCID,Case James Brett³^ORCID,Park Young-Jun⁴^ORCID,Cao Longxing⁴⁵^ORCID,Wu Kejia⁴⁵^ORCID,Walls Alexandra C.⁴⁶^ORCID,Liu Zhuoming⁷^ORCID,Bowen John E.⁴^ORCID,Yeh Hsien-Wei⁴⁵^ORCID,Saini Shally⁴⁸^ORCID,Helms Louisa⁸⁹¹⁰¹¹^ORCID,Zhao Yan Ting⁴⁸¹²^ORCID,Hsiang Tien-Ying¹³^ORCID,Starr Tyler N.¹⁴^ORCID,Goreshnik Inna⁴⁵^ORCID,Kozodoy Lisa⁴⁵,Carter Lauren⁴⁵^ORCID,Ravichandran Rashmi⁴⁵^ORCID,Green Lydia B.¹⁵,Matochko Wadim L.¹⁵^ORCID,Thomson Christy A.¹⁵,Vögeli Bastian¹²¹⁶^ORCID,Krüger Antje¹²^ORCID,VanBlargan Laura A.³^ORCID,Chen Rita E.³¹⁷^ORCID,Ying Baoling³^ORCID,Bailey Adam L.¹⁷¹⁸^ORCID,Kafai Natasha M.³¹⁷^ORCID,Boyken Scott E.⁴⁵^ORCID,Ljubetič Ajasja⁴⁵¹⁹^ORCID,Edman Natasha⁴⁵²⁰²¹^ORCID,Ueda George⁴⁵^ORCID,Chow Cameron M.⁴⁵²²^ORCID,Johnson Max⁴⁵^ORCID,Addetia Amin⁴²³^ORCID,Navarro Mary-Jane⁴^ORCID,Panpradist Nuttada²⁴^ORCID,Gale Michael¹³^ORCID,Freedman Benjamin S.⁸⁹¹⁰¹¹²⁴,Bloom Jesse D.⁶¹⁴²⁵^ORCID,Ruohola-Baker Hannele⁴⁸¹²²⁴^ORCID,Whelan Sean P. J.⁷^ORCID,Stewart Lance⁴⁵^ORCID,Diamond Michael S.³⁷¹⁷²⁶^ORCID,Veesler David⁴⁶^ORCID,Jewett Michael C.¹²²⁷²⁸^ORCID,Baker David⁴⁵⁶^ORCID

Affiliation:

1. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.

2. Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.

3. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

4. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

5. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.

6. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

7. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

8. Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.

9. Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.

10. Kidney Research Institute, University of Washington School of Medicine, Seattle, WA 98109, USA.

11. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA.

12. Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA 98195, USA.

13. Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA.

14. Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

15. Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.

16. Invizyne Technologies Inc., Monrovia, CA 91016, USA.

17. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

18. Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, WI 53705, USA.

19. Department for Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana SI-1000, Slovenia.

20. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.

21. USA Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.

22. Neolukin Therapeutics Inc., Seattle, WA 98102, USA.

23. Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.

24. Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.

25. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

26. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA.

27. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.

28. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Reference116 articles.

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