학술논문
Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice
Document Type
article
Author
Hunt, Andrew C; Case, James Brett; Park, Young-Jun; Cao, Longxing; Wu, Kejia; Walls, Alexandra C; Liu, Zhuoming; Bowen, John E; Yeh, Hsien-Wei; Saini, Shally; Helms, Louisa; Zhao, Yan Ting; Hsiang, Tien-Ying; Starr, Tyler N; Goreshnik, Inna; Kozodoy, Lisa; Carter, Lauren; Ravichandran, Rashmi; Green, Lydia B; Matochko, Wadim L; Thomson, Christy A; Vögeli, Bastian; Krüger, Antje; VanBlargan, Laura A; Chen, Rita E; Ying, Baoling; Bailey, Adam L; Kafai, Natasha M; Boyken, Scott E; Ljubetič, Ajasja; Edman, Natasha; Ueda, George; Chow, Cameron M; Johnson, Max; Addetia, Amin; Navarro, Mary Jane; Panpradist, Nuttada; Gale, Michael; Freedman, Benjamin S; Bloom, Jesse D; Ruohola-Baker, Hannele; Whelan, Sean PJ; Stewart, Lance; Diamond, Michael S; Veesler, David; Jewett, Michael C; Baker, David
Source
Science Translational Medicine. 14(646)
Subject
Language
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.