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TitleMultivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
Journal, issue, pagesSci Transl Med, Vol. 14, Issue 646, Page eabn1252, Year 2022
Publish dateMay 25, 2022
AuthorsAndrew C Hunt / James Brett Case / Young-Jun Park / Longxing Cao / Kejia Wu / Alexandra C Walls / Zhuoming Liu / John E Bowen / Hsien-Wei Yeh / Shally Saini / Louisa Helms / Yan Ting Zhao / Tien-Ying Hsiang / Tyler N Starr / Inna Goreshnik / Lisa Kozodoy / Lauren Carter / Rashmi Ravichandran / Lydia B Green / Wadim L Matochko / Christy A Thomson / Bastian Vögeli / Antje Krüger / Laura A VanBlargan / Rita E Chen / Baoling Ying / Adam L Bailey / Natasha M Kafai / Scott E Boyken / Ajasja Ljubetič / Natasha Edman / George Ueda / Cameron M Chow / Max Johnson / Amin Addetia / Mary-Jane Navarro / Nuttada Panpradist / Michael Gale / Benjamin S Freedman / Jesse D Bloom / Hannele Ruohola-Baker / Sean P J Whelan / Lance Stewart / Michael S Diamond / David Veesler / Michael C Jewett / David Baker /
PubMed AbstractNew 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 ...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.
External linksSci Transl Med / PubMed:35412328 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 5.2 Å
Structure data

EMDB-26507: SARS-CoV-2 spike in complex with Multivalent miniprotein inhibitor FUS231-P24 (2RBDs open)
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-26508: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
Method: EM (single particle) / Resolution: 5.2 Å

EMDB-26509: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS31-G10 (2RBDs open)
Method: EM (single particle) / Resolution: 4.57 Å

EMDB-26510: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS31-G10 (3RBDs open)
Method: EM (single particle) / Resolution: 4.65 Å

26511

7uhb

EMDB-26511, PDB-7uhb:
SARS-CoV-2 spike in complex with AHB2-2GS-SB175 (local refinement of the RBD and AHB2)
Method: EM (single particle) / Resolution: 3.0 Å

26512

7uhc

EMDB-26512, PDB-7uhc:
SARS-CoV-2 spike in complex with AHB2-2GS-SB175
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
  • severe acute respiratory syndrome coronavirus
KeywordsVIRAL PROTEIN / SARS-CoV-2 / COVID-19 / spike glycoprotein / fusion protein / neutralizing antibodies / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / Inhibitor / miniprotein inhibitor

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