{"doi":"10.17615/6j94-g634","title":"Engineering a “muco-trapping” ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19","abstract":"Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco-trapping” ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.","journal":"UNC Libraries","year":2024,"id":501757,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":394350,"name":"Whitney Wolf","orcid":null,"position":1,"is_corresponding":false},{"id":1351343,"name":"Lai S.K.","orcid":null,"position":2,"is_corresponding":false},{"id":65342,"name":"Axel Schaefer","orcid":null,"position":3,"is_corresponding":false},{"id":1351344,"name":"Hutchins J.T","orcid":null,"position":4,"is_corresponding":false},{"id":1351345,"name":"Ma A.","orcid":null,"position":5,"is_corresponding":false},{"id":1351346,"name":"Poon V.K.-M.","orcid":null,"position":6,"is_corresponding":false},{"id":803240,"name":"M.D. McSweeney","orcid":null,"position":7,"is_corresponding":false},{"id":585318,"name":"Shuiqiao Yuan","orcid":"0000-0003-1460-7682","position":8,"is_corresponding":false},{"id":738279,"name":"Priya A. Kumar","orcid":"0000-0003-1997-4086","position":9,"is_corresponding":false},{"id":1351044,"name":"H Arora","orcid":"0000-0003-3081-3320","position":10,"is_corresponding":false},{"id":1351347,"name":"Jean Edelstein","orcid":null,"position":11,"is_corresponding":false},{"id":1239779,"name":"Brian T. Farrer","orcid":null,"position":12,"is_corresponding":false},{"id":287221,"name":"Carlos Cruz‐Teran","orcid":null,"position":13,"is_corresponding":false},{"id":1351348,"name":"Chan J.F.-W.","orcid":null,"position":14,"is_corresponding":false},{"id":285631,"name":"Karthik Tiruthani","orcid":"0000-0002-8939-7774","position":15,"is_corresponding":false},{"id":1075627,"name":"Ian E. Stewart","orcid":"0000-0002-1752-632X","position":16,"is_corresponding":false},{"id":1351349,"name":"Chan C.C.S","orcid":null,"position":17,"is_corresponding":false},{"id":1351350,"name":"L Botta","orcid":null,"position":18,"is_corresponding":false},{"id":1351351,"name":"Yuen K.-Y.","orcid":null,"position":19,"is_corresponding":false},{"id":1351342,"name":"Hickey A.J.","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:15.999370Z","pmid":null,"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":[]}