{"id":"doi:10.1126/scitranslmed.abn1252","kind":"article","title":"Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice","authors":["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","Vögeli B","Krüger A","VanBlargan LA","Chen RE"],"author_count":47,"year":2022,"published":"2022-05-25","venue":"Science translational medicine","cited_by":108,"doi":"10.1126/scitranslmed.abn1252","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1126/scitranslmed.abn1252","archive_url":"https://space-kitty.com/papers/doi:10.1126/scitranslmed.abn1252","updated":null,"pmid":"35412328","pmcid":"PMC9258422","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9258422/pdf","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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice\" by Hunt AC, Case JB, Park YJ et al., https://doi.org/10.1126/scitranslmed.abn1252, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"synthetic-biology","name":"Synthetic Biology & Genome Engineering","domain_slug":"biotech"}],"cited_in_dossiers":[{"slug":"synthetic-biology","title":"Synthetic Biology & Genome Engineering: State of the Field (October 2026)","url":"https://space-kitty.com/dossiers/synthetic-biology"}]}