{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T02:16:58Z","timestamp":1794363418290,"version":"4.9.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009318","name":"Helmholtz Association","doi-asserted-by":"publisher","award":["FISCOV"],"award-info":[{"award-number":["FISCOV"]}],"id":[{"id":"10.13039\/501100009318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009318","name":"Helmholtz Association","doi-asserted-by":"publisher","award":["SFragX"],"award-info":[{"award-number":["SFragX"]}],"id":[{"id":"10.13039\/501100009318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["\u201cConScience\u201d (project 16GW0277)"],"award-info":[{"award-number":["\u201cConScience\u201d (project 16GW0277)"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M<jats:sup>pro<\/jats:sup>), its moderate activity in M<jats:sup>pro<\/jats:sup> inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin\u2019s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1\u2009mg\/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.<\/jats:p>","DOI":"10.1038\/s42003-023-05317-9","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T16:06:46Z","timestamp":1697645206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7354-0839","authenticated-orcid":false,"given":"Patrick Y. A.","family":"Reinke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmarcia Elisa","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-6653","authenticated-orcid":false,"given":"Sebastian","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-1791","authenticated-orcid":false,"given":"Sven","family":"Falke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-5082","authenticated-orcid":false,"given":"Julia","family":"Lieske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8626-4864","authenticated-orcid":false,"given":"Wiebke","family":"Ewert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9601-3484","authenticated-orcid":false,"given":"Jure","family":"Loboda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2749-9003","authenticated-orcid":false,"given":"Alexander","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9177-5589","authenticated-orcid":false,"given":"Aida","family":"Rahmani Mashhour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7033-9224","authenticated-orcid":false,"given":"Katarina","family":"Karni\u010dar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-2886","authenticated-orcid":false,"given":"Aleksandra","family":"Usenik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7681-3436","authenticated-orcid":false,"given":"Nata\u0161a","family":"Lindi\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreja","family":"Sekirnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-3687","authenticated-orcid":false,"given":"Viviane Fongaro","family":"Botosso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gl\u00e1ucia Maria Machado","family":"Santelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2182-4549","authenticated-orcid":false,"given":"Josana","family":"Kapronezai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-3225","authenticated-orcid":false,"given":"Marcelo Valdemir","family":"de Ara\u00fajo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiana Tain\u00e1","family":"Silva-Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4728-1228","authenticated-orcid":false,"given":"Ant\u00f4nio Francisco de Souza","family":"Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Silva","family":"Tavares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizdany","family":"Fl\u00f3rez-\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0534-0886","authenticated-orcid":false,"given":"Danielle Bruna Leal","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edison Luiz","family":"Durigon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2261-281X","authenticated-orcid":false,"given":"Paula Roberta","family":"Giaretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6444-9788","authenticated-orcid":false,"given":"Marcos Bryan","family":"Heinemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Seychell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"B\u00f6hler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wioletta","family":"Rut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8510-1967","authenticated-orcid":false,"given":"Marcin","family":"Drag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7398-3982","authenticated-orcid":false,"given":"Tobias","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-0157","authenticated-orcid":false,"given":"Russell","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-1743","authenticated-orcid":false,"given":"Henry N.","family":"Chapman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3879-5019","authenticated-orcid":false,"given":"Christian","family":"Betzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Brehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-4565","authenticated-orcid":false,"given":"Winfried","family":"Hinrichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-3037","authenticated-orcid":false,"given":"Gregor","family":"Ebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharissa L.","family":"Latham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-5863","authenticated-orcid":false,"given":"Ana Marcia de S\u00e1","family":"Guimar\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0205-6609","authenticated-orcid":false,"given":"Dusan","family":"Turk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5987-1749","authenticated-orcid":false,"given":"Carsten","family":"Wrenger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6078-4095","authenticated-orcid":false,"given":"Alke","family":"Meents","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"5317_CR1","first-page":"eabq4064","volume":"0","author":"M Sasaki","year":"2022","unstructured":"Sasaki, M. et al. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters. Sci. Transl. Med. 0, eabq4064 (2022).","journal-title":"Sci. Transl. Med."},{"key":"5317_CR2","doi-asserted-by":"crossref","unstructured":"Iketani, S. et al. Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir. Nature 613, 558\u2013564 (2022).","DOI":"10.1038\/s41586-022-05514-2"},{"key":"5317_CR3","doi-asserted-by":"crossref","unstructured":"Hu, Y. et al. Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir. ACS Cent Sci. 24, 1658\u20131669 (2023).","DOI":"10.1021\/acscentsci.3c00538"},{"key":"5317_CR4","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1126\/science.abf7945","volume":"372","author":"S G\u00fcnther","year":"2021","unstructured":"G\u00fcnther, S. et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science 372, 642\u2013646 (2021).","journal-title":"Science"},{"key":"5317_CR5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.slasd.2021.10.012","volume":"27","author":"S Mediouni","year":"2022","unstructured":"Mediouni, S. et al. Identification of potent small molecule inhibitors of SARS-CoV-2 entry. SLAS Discov. 27, 8\u201319 (2022).","journal-title":"SLAS Discov."},{"key":"5317_CR6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.slasd.2021.12.005","volume":"27","author":"M Xu","year":"2022","unstructured":"Xu, M. et al. A high throughput screening assay for inhibitors of SARS-CoV-2 pseudotyped particle entry. SLAS Discov. 27, 86\u201394 (2022).","journal-title":"SLAS Discov."},{"key":"5317_CR7","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1016\/j.csbj.2022.05.023","volume":"20","author":"W-L Yang","year":"2022","unstructured":"Yang, W.-L. et al. Potential drug discovery for COVID-19 treatment targeting Cathepsin L using a deep learning-based strategy. Comput Struct. Biotechnol. J. 20, 2442\u20132454 (2022).","journal-title":"Comput Struct. Biotechnol. J."},{"key":"5317_CR8","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1007\/s10787-022-01002-1","volume":"30","author":"AD Juibari","year":"2022","unstructured":"Juibari, A. D., Rezadoost, M. H. & Soleimani, M. The key role of Calpain in COVID-19 as a therapeutic strategy. Inflammopharmacology 30, 1479\u20131491 (2022).","journal-title":"Inflammopharmacology"},{"key":"5317_CR9","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41422-020-0356-z","volume":"30","author":"C Ma","year":"2020","unstructured":"Ma, C. et al. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res. 30, 678\u2013692 (2020).","journal-title":"Cell Res."},{"key":"5317_CR10","doi-asserted-by":"crossref","first-page":"eabe0751","DOI":"10.1126\/sciadv.abe0751","volume":"6","author":"MD Sacco","year":"2020","unstructured":"Sacco, M. D. et al. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L. Sci. Adv. 6, eabe0751 (2020).","journal-title":"Sci. Adv."},{"key":"5317_CR11","doi-asserted-by":"crossref","first-page":"R1589","DOI":"10.1152\/ajpregu.00668.2005","volume":"290","author":"MU Fareed","year":"2006","unstructured":"Fareed, M. U. et al. Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1\/MAFbx and MuRF1 expression. Am. J. Physiol. Regulat. Integr. Comp. Physiol. 290, R1589\u2013R1597 (2006).","journal-title":"Am. J. Physiol. Regulat. Integr. Comp. Physiol."},{"key":"5317_CR12","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.tips.2004.04.001","volume":"25","author":"AJ Turner","year":"2004","unstructured":"Turner, A. J. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharm. Sci. 25, 291\u2013294 (2004).","journal-title":"Trends Pharm. Sci."},{"key":"5317_CR13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","volume":"23","author":"CB Jackson","year":"2022","unstructured":"Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 23, 3\u201320 (2022).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"5317_CR14","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","volume":"581","author":"J Shang","year":"2020","unstructured":"Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221\u2013224 (2020).","journal-title":"Nature"},{"key":"5317_CR15","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271\u2013280 (2020).","journal-title":"Cell"},{"key":"5317_CR16","doi-asserted-by":"crossref","first-page":"100306","DOI":"10.1016\/j.jbc.2021.100306","volume":"296","author":"A Bayati","year":"2021","unstructured":"Bayati, A., Kumar, R., Francis, V. & McPherson, P. S. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J. Biol. Chem. 296, 100306 (2021).","journal-title":"J. Biol. Chem."},{"key":"5317_CR17","doi-asserted-by":"crossref","first-page":"e107821","DOI":"10.15252\/embj.2021107821","volume":"40","author":"J Koch","year":"2021","unstructured":"Koch, J. et al. TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells. EMBO J. 40, e107821 (2021).","journal-title":"EMBO J."},{"key":"5317_CR18","doi-asserted-by":"crossref","first-page":"100306","DOI":"10.1016\/j.jbc.2021.100306","volume":"296","author":"A Bayati","year":"2021","unstructured":"Bayati, A. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J. Biol. Chem. 296, 100306 (2021).","journal-title":"J. Biol. Chem."},{"key":"5317_CR19","doi-asserted-by":"crossref","unstructured":"Tu\u0161ar et al. Proteomic data and structure analysis combined reveal interplay of structural rigidity and flexibility on selectivity of cysteine cathepsins. Commun Biol. 24, 450 (2023).","DOI":"10.1038\/s42003-023-04772-8"},{"key":"5317_CR20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-020-00451-w","volume":"6","author":"M-M Zhao","year":"2021","unstructured":"Zhao, M.-M. et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal Transduct. Target. Ther. 6, 1\u201312 (2021).","journal-title":"Signal Transduct. Target. Ther."},{"key":"5317_CR21","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/pro.4073","volume":"30","author":"K Bollavaram","year":"2021","unstructured":"Bollavaram, K. et al. Multiple sites on SARS-CoV-2 spike protein are susceptible to proteolysis by cathepsins B, K, L, S, and V. Protein Sci. 30, 1131\u20131143 (2021).","journal-title":"Protein Sci."},{"key":"5317_CR22","doi-asserted-by":"crossref","first-page":"8887","DOI":"10.1128\/JVI.00415-08","volume":"82","author":"BJ Bosch","year":"2008","unstructured":"Bosch, B. J., Bartelink, W. & Rottier, P. J. M. Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide. J. Virol. 82, 8887\u20138890 (2008).","journal-title":"J. Virol."},{"key":"5317_CR23","doi-asserted-by":"crossref","first-page":"e202100456","DOI":"10.1002\/cmdc.202100456","volume":"17","author":"XR Ma","year":"2022","unstructured":"Ma, X. R. et al. MPI8 is potent against SARS-CoV-2 by inhibiting dually and selectively the SARS-CoV-2 main protease and the host Cathepsin L. ChemMedChem 17, e202100456 (2022).","journal-title":"ChemMedChem"},{"key":"5317_CR24","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1021\/acsinfecdis.0c00761","volume":"7","author":"Y Hu","year":"2021","unstructured":"Hu, Y. et al. Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses. ACS Infect. Dis. 7, 586\u2013597 (2021).","journal-title":"ACS Infect. Dis."},{"key":"5317_CR25","doi-asserted-by":"crossref","first-page":"21035","DOI":"10.1021\/jacs.2c04626","volume":"144","author":"S Mondal","year":"2022","unstructured":"Mondal, S. et al. Dual inhibitors of main protease (MPro) and Cathepsin L as potent antivirals against SARS-CoV2. J. Am. Chem. Soc. 144, 21035\u201321045 (2022).","journal-title":"J. Am. Chem. Soc."},{"key":"5317_CR26","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1042\/CS20220638","volume":"136","author":"J Inal","year":"2022","unstructured":"Inal, J., Paizuldaeva, A. & Terziu, E. Therapeutic use of calpeptin in COVID-19 infection. Clin. Sci. 136, 1439\u20131447 (2022).","journal-title":"Clin. Sci."},{"key":"5317_CR27","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1021\/acs.jmedchem.7b00497","volume":"60","author":"AC Galasiti Kankanamalage","year":"2017","unstructured":"Galasiti Kankanamalage, A. C. et al. Design, synthesis, and evaluation of novel prodrugs of transition state inhibitors of norovirus 3CL protease. J. Med Chem. 60, 6239\u20136248 (2017).","journal-title":"J. Med Chem."},{"key":"5317_CR28","doi-asserted-by":"crossref","first-page":"e2000246","DOI":"10.1002\/pmic.202000246","volume":"21","author":"T Koudelka","year":"2021","unstructured":"Koudelka, T. et al. N-terminomics for the identification of in vitro substrates and cleavage site specificity of the SARS-CoV-2 main protease. Proteomics 21, e2000246 (2021).","journal-title":"Proteomics"},{"key":"5317_CR29","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.1021\/pr200621z","volume":"10","author":"ML Biniossek","year":"2011","unstructured":"Biniossek, M. L., N\u00e4gler, D. K., Becker-Pauly, C. & Schilling, O. Proteomic identification of protease cleavage sites characterizes prime and non-prime specificity of cysteine cathepsins B, L, and S. J. Proteome Res. 10, 5363\u20135373 (2011).","journal-title":"J. Proteome Res."},{"key":"5317_CR30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0065-2571(01)00034-6","volume":"42","author":"V Turk","year":"2002","unstructured":"Turk, V., Turk, B., Guncar, G., Turk, D. & Kos, J. Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer. Adv. Enzym. Regul. 42, 285\u2013303 (2002).","journal-title":"Adv. Enzym. Regul."},{"key":"5317_CR31","volume":"8","author":"C Sakuma","year":"2018","unstructured":"Sakuma, C. et al. Novel endogenous simian retroviral integrations in Vero cells: implications for quality control of a human vaccine cell substrate. Sci. Rep. 8, 644 (2018).","journal-title":"Sci. Rep."},{"key":"5317_CR32","doi-asserted-by":"crossref","first-page":"e200342","DOI":"10.1590\/0074-02760200342","volume":"115","author":"DB Araujo","year":"2020","unstructured":"Araujo, D. B. et al. SARS-CoV-2 isolation from the first reported patients in Brazil and establishment of a coordinated task network. Mem. Inst. Oswaldo Cruz 115, e200342 (2020).","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"5317_CR33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.coviro.2021.03.009","volume":"48","author":"C-Y Lee","year":"2021","unstructured":"Lee, C.-Y. & Lowen, A. C. Animal models for SARS-CoV-2. Curr. Opin. Virol. 48, 73\u201381 (2021).","journal-title":"Curr. Opin. Virol."},{"key":"5317_CR34","volume":"11","author":"W Vuong","year":"2020","unstructured":"Vuong, W. et al. Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat. Commun. 11, 4282 (2020).","journal-title":"Nat. Commun."},{"key":"5317_CR35","doi-asserted-by":"crossref","first-page":"e1005531","DOI":"10.1371\/journal.ppat.1005531","volume":"12","author":"Y Kim","year":"2016","unstructured":"Kim, Y. et al. Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog. 12, e1005531 (2016).","journal-title":"PLoS Pathog."},{"key":"5317_CR36","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1165\/rcmb.2020-0280LE","volume":"63","author":"AD Gruber","year":"2020","unstructured":"Gruber, A. D. et al. Standardization of reporting criteria for lung pathology in SARS-CoV-2\u2013infected hamsters: what matters? Am. J. Respir. Cell Mol. Biol. 63, 856\u2013859 (2020).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"5317_CR37","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S0006-291X(88)81355-X","volume":"153","author":"T Tsujinaka","year":"1988","unstructured":"Tsujinaka, T. et al. Synthesis of a new cell penetrating calpain inhibitor (calpeptin). Biochem. Biophys. Res. Commun. 153, 1201\u20131208 (1988).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"5317_CR38","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1002\/jnr.22408","volume":"88","author":"MK Guyton","year":"2010","unstructured":"Guyton, M. K. et al. Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis. J. Neurosci. Res. 88, 2398\u20132408 (2010).","journal-title":"J. Neurosci. Res."},{"key":"5317_CR39","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1111\/cas.13024","volume":"107","author":"M Yoshida","year":"2016","unstructured":"Yoshida, M. et al. Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model. Cancer Sci. 107, 1443\u20131452 (2016).","journal-title":"Cancer Sci."},{"key":"5317_CR40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tox.2018.03.003","volume":"400\u2013401","author":"B Su","year":"2018","unstructured":"Su, B. et al. Calpeptin is neuroprotective against acrylamide-induced neuropathy in rats. Toxicology 400\u2013401, 1\u20138 (2018).","journal-title":"Toxicology"},{"key":"5317_CR41","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1042\/BCJ20210197","volume":"478","author":"JC Milligan","year":"2021","unstructured":"Milligan, J. C. et al. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease. Biochem. J. 478, 2499\u20132515 (2021).","journal-title":"Biochem. J."},{"key":"5317_CR42","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1021\/jm020238t","volume":"45","author":"SF Chowdhury","year":"2002","unstructured":"Chowdhury, S. F. et al. Design of noncovalent inhibitors of human Cathepsin L. From the 96-residue proregion to optimized tripeptides. J. Med. Chem. 45, 5321\u20135329 (2002).","journal-title":"J. Med. Chem."},{"key":"5317_CR43","doi-asserted-by":"crossref","first-page":"8722","DOI":"10.1128\/JVI.00253-07","volume":"81","author":"Y Inoue","year":"2007","unstructured":"Inoue, Y. et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J. Virol. 81, 8722\u20138729 (2007).","journal-title":"J. Virol."},{"key":"5317_CR44","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1126\/science.1110656","volume":"308","author":"K Chandran","year":"2005","unstructured":"Chandran, K., Sullivan, N. J., Felbor, U., Whelan, S. P. & Cunningham, J. M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308, 1643\u20131645 (2005).","journal-title":"Science"},{"key":"5317_CR45","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1126\/science.abb3753","volume":"370","author":"A Bruchez","year":"2020","unstructured":"Bruchez, A. et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science 370, 241\u2013247 (2020).","journal-title":"Science"},{"key":"5317_CR46","doi-asserted-by":"crossref","first-page":"14453","DOI":"10.1074\/jbc.M801283200","volume":"283","author":"M Mihelic","year":"2008","unstructured":"Mihelic, M., Dobersek, A., Guncar, G. & Turk, D. Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation. J. Biol. Chem. 283, 14453\u201314460 (2008).","journal-title":"J. Biol. Chem."},{"key":"5317_CR47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pep.2011.11.002","volume":"82","author":"M Novinec","year":"2012","unstructured":"Novinec, M., Pav\u0161i\u010d, M. & Lenar\u010di\u010d, B. A simple and efficient protocol for the production of recombinant cathepsin V and other cysteine cathepsins in soluble form in Escherichia coli. Protein Expr. Purif. 82, 1\u20135 (2012).","journal-title":"Protein Expr. Purif."},{"key":"5317_CR48","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1021\/jacs.8b11027","volume":"141","author":"E Mons","year":"2019","unstructured":"Mons, E. et al. The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K. J. Am. Chem. Soc. 141, 3507\u20133514 (2019).","journal-title":"J. Am. Chem. Soc."},{"key":"5317_CR49","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","volume":"368","author":"L Zhang","year":"2020","unstructured":"Zhang, L. et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors. Science 368, 409\u2013412 (2020).","journal-title":"Science"},{"key":"5317_CR50","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41589-020-00689-z","volume":"17","author":"W Rut","year":"2021","unstructured":"Rut, W. et al. SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging. Nat. Chem. Biol. 17, 222\u2013228 (2021).","journal-title":"Nat. Chem. Biol."},{"key":"5317_CR51","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41586-021-03493-4","volume":"594","author":"A Stukalov","year":"2021","unstructured":"Stukalov, A. et al. Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 594, 246\u2013252 (2021).","journal-title":"Nature"},{"key":"5317_CR52","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-020-2294-9","volume":"582","author":"T Thi Nhu Thao","year":"2020","unstructured":"Thi Nhu Thao, T. et al. Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform. Nature 582, 561\u2013565 (2020).","journal-title":"Nature"},{"key":"5317_CR53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0309-1651(91)90155-C","volume":"15","author":"M Bonaldo","year":"1991","unstructured":"Bonaldo, M. et al. Comparative characterization of a human large cell lung carcinoma cell line and the xenograft derived cell line. Cell Biol. Int. Rep. 15, 229\u2013241 (1991).","journal-title":"Cell Biol. Int. Rep."},{"key":"5317_CR54","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s004180100262","volume":"115","author":"R Manelli-Oliveira","year":"2001","unstructured":"Manelli-Oliveira, R. & Machado-Santelli, G. M. Cytoskeletal and nuclear alterations in human lung tumor cells: a confocal microscope study. Histochem. Cell Biol. 115, 403\u2013411 (2001).","journal-title":"Histochem. Cell Biol."},{"key":"5317_CR55","doi-asserted-by":"crossref","first-page":"8979","DOI":"10.18632\/oncotarget.6924","volume":"7","author":"BA Cortez","year":"2016","unstructured":"Cortez, B. A., Rezende-Teixeira, P., Redick, S., Doxsey, S. & Machado-Santelli, G. M. Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression. Oncotarget 7, 8979\u20138992 (2016).","journal-title":"Oncotarget"},{"key":"5317_CR56","first-page":"2000045","volume":"25","author":"VM Corman","year":"2020","unstructured":"Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25, 2000045 (2020).","journal-title":"Eurosurveillance"},{"key":"5317_CR57","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1177\/1087057106296688","volume":"12","author":"WE Severson","year":"2007","unstructured":"Severson, W. E. et al. Development and validation of a high-throughput screen for inhibitors of SARS CoV and its application in screening of a 100,000-compound library. J. Biomol. Screen. 12, 33\u201340 (2007).","journal-title":"J. Biomol. Screen."},{"key":"5317_CR58","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1038\/emboj.2011.286","volume":"30","author":"J Huotari","year":"2011","unstructured":"Huotari, J. & Helenius, A. Endosome maturation. EMBO J. 30, 3481\u20133500 (2011).","journal-title":"EMBO J."},{"key":"5317_CR59","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1107\/S0907444913008408","volume":"69","author":"D Turk","year":"2013","unstructured":"Turk, D. MAIN software for density averaging, model building, structure refinement and validation. Acta Cryst. D 69, 1342\u20131357 (2013).","journal-title":"Acta Cryst. D"},{"key":"5317_CR60","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"5317_CR61","doi-asserted-by":"crossref","unstructured":"Hierholzer, J. C. & Killington, R. A. in Virology Methods Manual 25\u201346 (Elsevier, 1996).","DOI":"10.1016\/B978-012465330-6\/50003-8"},{"key":"5317_CR62","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-07793-1","volume":"12","author":"VF Botosso","year":"2022","unstructured":"Botosso, V. F. et al. Anti-SARS-CoV-2 equine F (Ab\u2019)2 immunoglobulin as a possible therapy for COVID-19. Sci. Rep. 12, 3890 (2022).","journal-title":"Sci. Rep."},{"key":"5317_CR63","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1073\/pnas.2009799117","volume":"117","author":"M Imai","year":"2020","unstructured":"Imai, M. et al. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc. Natl Acad. Sci. USA 117, 16587\u201316595 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5317_CR64","first-page":"2428","volume":"71","author":"JF-W Chan","year":"2020","unstructured":"Chan, J. F.-W. et al. Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) in a Golden Syrian Hamster Model: implications for disease pathogenesis and transmissibility. Clin. Infect. Dis. 71, 2428\u20132446 (2020).","journal-title":"Clin. Infect. Dis."},{"key":"5317_CR65","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1111\/tbed.13907","volume":"68","author":"K Pandey","year":"2021","unstructured":"Pandey, K. et al. Animal models for SARS-CoV-2 research: a comprehensive literature review. Transbound. Emerg. Dis. 68, 1868\u20131885 (2021).","journal-title":"Transbound. Emerg. Dis."},{"key":"5317_CR66","doi-asserted-by":"crossref","first-page":"167003","DOI":"10.1016\/j.jmb.2021.167003","volume":"433","author":"E Arutyunova","year":"2021","unstructured":"Arutyunova, E. et al. N-terminal finger stabilizes the S1 pocket for the reversible feline drug GC376 in the SARS-CoV-2 Mpro dimer. J. Mol. Biol. 433, 167003 (2021).","journal-title":"J. Mol. Biol."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05317-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05317-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05317-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T13:31:25Z","timestamp":1700141485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05317-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,18]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["5317"],"URL":"https:\/\/doi.org\/10.1038\/s42003-023-05317-9","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,18]]},"assertion":[{"value":"12 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1058"}}