{"doi":"10.1038/s42003-023-04860-9","title":"A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo","abstract":"SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate to evade monoclonal antibodies and antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works by binding the SARS-CoV-2 S protein, acting as a 'decoy' to block the interaction between the S and human ACE2. Using a computational design strategy, we designed an affinity-enhanced ACE2 decoy, FLIF, that exhibited tight binding to SARS-CoV-2 delta and omicron variants. Our computationally calculated absolute binding free energies (ABFE) between sACE2:SARS-CoV-2 S proteins and their variants showed excellent agreement to binding experiments. FLIF displayed robust therapeutic utility against a broad range of SARS-CoV-2 variants and sarbecoviruses, and neutralized omicron BA.5 in vitro and in vivo. Furthermore, we directly compared the in vivo therapeutic efficacy of wild-type ACE2 (non-affinity enhanced ACE2) against FLIF. A few wild-type sACE2 decoys have shown to be effective against early circulating variants such as Wuhan in vivo. Our data suggest that moving forward, affinity-enhanced ACE2 decoys like FLIF may be required to combat evolving SARS-CoV-2 variants. The approach described herein emphasizes how computational methods have become sufficiently accurate for the design of therapeutics against viral protein targets. Affinity-enhanced ACE2 decoys remain highly effective at neutralizing omicron subvariants.","journal":"Communications Biology","year":2023,"id":336233,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1067127,"name":"Graeme Walker Lindsey","orcid":null,"position":1,"is_corresponding":false},{"id":747357,"name":"Yusuke Higuchi","orcid":"0000-0002-5982-9660","position":2,"is_corresponding":false},{"id":1066658,"name":"Yumi Itoh","orcid":"0000-0001-5501-3413","position":3,"is_corresponding":false},{"id":1037761,"name":"Tatsuya Suzuki","orcid":"0000-0002-1437-2273","position":4,"is_corresponding":false},{"id":1066659,"name":"Toru Okamoto","orcid":"0000-0003-4000-3102","position":5,"is_corresponding":false},{"id":849952,"name":"Atsushi Hoshino","orcid":"0000-0002-4015-1319","position":6,"is_corresponding":false},{"id":343873,"name":"Erik Procko","orcid":"0000-0002-0028-490X","position":7,"is_corresponding":false},{"id":415532,"name":"Shahidul M. Islam","orcid":"0000-0001-5769-6844","position":8,"is_corresponding":false},{"id":1066657,"name":"Brandon Havranek","orcid":"0000-0003-4397-684X","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":null,"created_at":"2026-07-19T01:10:17.243221Z","pmid":"37173421","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}