EMD-26512
SARS-CoV-2 spike in complex with AHB2-2GS-SB175
EMD-26512
Single-particle3.1 Å
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Map released: 08/06/2022
Last modified: 30/10/2024
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
synthetic construct
Sample: SARS-CoV-2 spike in complex with multivalent minibinder AHB2-2GS-SB175
Fitted models: 7uhc (Avg. Q-score: 0.465)
Deposition Authors: Park YJ
,
Seattle Structural Genomics Center for Infectious Disease (SSGCID),
Veesler D
Sample: SARS-CoV-2 spike in complex with multivalent minibinder AHB2-2GS-SB175
Fitted models: 7uhc (Avg. Q-score: 0.465)
Deposition Authors: Park YJ
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Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
Hunt AC
,
Case JB
,
Park YJ
,
Cao L
,
Wu K
,
Walls AC
,
Liu Z
,
Bowen JE
,
Yeh HW
,
Saini S
,
Helms L
,
Zhao YT
,
Hsiang TY
,
Starr TN
,
Goreshnik I
,
Kozodoy L,
Carter L
,
Ravichandran R
,
Green LB,
Matochko WL
,
Thomson CA,
Vogeli B
,
Kruger A
,
VanBlargan LA
,
Chen RE
,
Ying B
,
Bailey AL
,
Kafai NM
,
Boyken SE
,
Ljubetic A
,
Edman N
,
Ueda G
,
Chow CM
,
Johnson M
,
Addetia A
,
Navarro MJ
,
Panpradist N
,
Gale Jr M
,
Freedman BS,
Bloom JD
,
Ruohola-Baker H
,
Whelan SPJ
,
Stewart L
,
Diamond MS
,
Veesler D
,
Jewett MC
,
Baker D
(2022) Sci Transl Med , 14 , eabn1252 - eabn1252
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(2022) Sci Transl Med , 14 , eabn1252 - eabn1252
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.
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.