{"doi":"10.1101/2021.06.07.447437","title":"FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant","abstract":"Abstract The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 in vivo and in vitro . The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218964,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"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":629702,"name":"Jing Wang","orcid":"0000-0002-9084-9985","position":1,"is_corresponding":false},{"id":817110,"name":"Lei Tian","orcid":"0000-0002-9051-9468","position":2,"is_corresponding":false},{"id":374845,"name":"Jianying Zhang","orcid":"0000-0001-5896-9509","position":3,"is_corresponding":false},{"id":434529,"name":"Heather Mead","orcid":"0000-0002-5680-0758","position":4,"is_corresponding":false},{"id":576454,"name":"Sierra A. Jaramillo","orcid":null,"position":5,"is_corresponding":false},{"id":280680,"name":"Aimin Li","orcid":"0000-0002-6983-2310","position":6,"is_corresponding":false},{"id":105523,"name":"Ross E. Zumwalt","orcid":null,"position":7,"is_corresponding":false},{"id":103752,"name":"Sean P. J. Whelan","orcid":"0000-0003-1564-8590","position":8,"is_corresponding":false},{"id":482796,"name":"Erik W. Settles","orcid":"0000-0003-4331-3683","position":9,"is_corresponding":false},{"id":380251,"name":"Paul Keim","orcid":"0000-0003-0089-5820","position":10,"is_corresponding":false},{"id":316384,"name":"Bridget M. Barker","orcid":"0000-0002-3439-4517","position":11,"is_corresponding":false},{"id":3645,"name":"Michael A. Caligiuri","orcid":"0000-0002-4095-3020","position":12,"is_corresponding":false},{"id":253516,"name":"Jianhua Yu","orcid":"0000-0002-0326-3223","position":13,"is_corresponding":false},{"id":374844,"name":"Wenjuan Dong","orcid":"0000-0002-4110-424X","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:33.915158Z","pmid":"34127969","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":[]}