{"doi":"10.1101/2021.07.07.451375","title":"Multivalent designed proteins protect against SARS-CoV-2 variants of concern","abstract":"Abstract Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC 50 values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness. One-Sentence Summary We designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213597,"datarank":0.44166584687496613,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.0,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":106498,"name":"James Brett Case","orcid":"0000-0001-7331-5511","position":1,"is_corresponding":false},{"id":97052,"name":"Young‐Jun Park","orcid":"0000-0003-2901-6949","position":2,"is_corresponding":false},{"id":218557,"name":"Longxing Cao","orcid":"0000-0003-4002-3648","position":3,"is_corresponding":false},{"id":805630,"name":"Kejia Wu","orcid":"0000-0002-4532-4290","position":4,"is_corresponding":false},{"id":97046,"name":"Alexandra C. 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