{"doi":"10.1101/2020.05.04.077826","title":"Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2","abstract":"Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. The main cellular location where the SARS-CoV-2 S protein priming occurs remains debatable, therefore hampering the development of targeted treatments. Herein, we identified the human extracellular serine protease inhibitor (serpin) alpha 1 antitrypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease-inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Our data support the key role of extracellular serine proteases in SARS-CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells. SUMMARY: Delivery of extracellular serine protease inhibitors (serpins) such as A1AT has the capacity to reduce SARS-CoV-2 dissemination by binding and inhibiting extracellular proteases on the host cells, thus, inhibiting the first step in SARS-CoV-2 cell cycle (i.e. cell entry).","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":118651,"datarank":0.5897738449086489,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":0.0,"self_endowment_contribution":0.5897738449086489,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":278067,"name":"Andrea M. Klingler","orcid":"0000-0003-0654-9996","position":1,"is_corresponding":false},{"id":397382,"name":"Victoria Callahan","orcid":"0000-0003-4615-9263","position":2,"is_corresponding":false},{"id":126183,"name":"Ivan Akhrymuk","orcid":null,"position":3,"is_corresponding":false},{"id":551712,"name":"Katarina Elez","orcid":"0000-0002-6160-8701","position":4,"is_corresponding":false},{"id":278064,"name":"Lluı́s Raich","orcid":"0000-0002-5493-6205","position":5,"is_corresponding":false},{"id":330791,"name":"Brandon Michael Henry","orcid":"0000-0002-8047-338X","position":6,"is_corresponding":false},{"id":330796,"name":"Justin L. Benoit","orcid":"0000-0002-0669-2963","position":7,"is_corresponding":false},{"id":330792,"name":"Stefanie W. Benoit","orcid":"0000-0002-4203-1978","position":8,"is_corresponding":false},{"id":278068,"name":"Frank Noé","orcid":"0000-0003-4169-9324","position":9,"is_corresponding":false},{"id":124326,"name":"Kylene Kehn-Hall","orcid":"0000-0001-8036-7213","position":10,"is_corresponding":false},{"id":237537,"name":"Marc E. Rothenberg","orcid":"0000-0001-9790-6332","position":11,"is_corresponding":false},{"id":278066,"name":"Nurit P. Azouz","orcid":"0000-0003-4969-1263","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:14:03.409507Z","pmid":"33052338","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":[]}