{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:02:00Z","timestamp":1770285720841,"version":"3.49.0"},"reference-count":19,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nazarbayev University Faculty of Development","award":["280720FD1907"],"award-info":[{"award-number":["280720FD1907"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The prevalence of novel SARS-CoV-2 variants is also accompanied by an increased turnover rate and additional cleavage sites at the positions necessary for priming the Spike (S) protein. Of these priming sites, the proteolytically sensitive polybasic sequence of the activation loop at the S1\/S2 interface and the S2\u2032 location within the S2 subunit of the S protein are cleaved by furin and TMPRSS2, which are important for the infection of the target cell. Neutrophils, migrating to the site of infection, secrete serine proteases to fight against pathogens. The serine proteases encompass neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG), which can hydrolyze the peptide bond adjacent to the S1\/S2 interface. SARS-CoV-2 might take the opportunity to hijack proteases from an immune response to support viral entry to the cell. The region near S704L within the S2 subunit, a novel amino acid substitution of SARS-CoV-2 Omicron sublineage BA.2.12.1, is located close to the S1\/S2 interface. We found that NE, PR3, and CatG digested the peptide within this region; however, the S704L amino acid substitution altered cleavage sites for PR3. In conclusion, such an amino acid substitution modifies S2 antigen processing and might further impact the major histocompatibility complex (MHC) binding and T cell activation.<\/jats:p>","DOI":"10.3390\/molecules27185817","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T07:05:56Z","timestamp":1662620756000},"page":"5817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Variation of Proteolytic Cleavage Sites towards the N-Terminal End of the S2 Subunit of the Novel SARS-CoV-2 Omicron Sublineage BA.2.12.1"],"prefix":"10.3390","volume":"27","author":[{"given":"Nadine Anna","family":"Schilling","sequence":"first","affiliation":[{"name":"Faculty of Organic Chemistry, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hubert","family":"Kalbacher","sequence":"additional","affiliation":[{"name":"Institute of Clinical Anatomy and Cell Analysis, Faculty of Medicine, Eberhard Karls University T\u00fcbingen, \u00d6sterbergstra\u00dfe 3, 72074 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-6558","authenticated-orcid":false,"given":"Timo","family":"Burster","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Sciences and Humanities, Nazarbayev University, Kabanbay Batyr Ave. 53, Nur-Sultan 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00705-022-05365-2","article-title":"The ins and outs of SARS-CoV-2 variants of concern (VOCs)","volume":"167","author":"Fazlalipour","year":"2022","journal-title":"Arch. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mustafa, Z., Kalbacher, H., and Burster, T. (2022). Occurrence of a novel cleavage site for cathepsin G adjacent to the polybasic sequence within the proteolytically sensitive activation loop of the SARS-CoV-2 Omicron variant: The amino acid substitution N679K and P681H of the spike protein. PloS ONE, 17.","DOI":"10.1371\/journal.pone.0264723"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"110829","DOI":"10.1016\/j.celrep.2022.110829","article-title":"Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant","volume":"39","author":"Liu","year":"2022","journal-title":"Cell Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/1348-0421.12945","article-title":"Proteolytic activation of SARS-CoV-2 spike protein","volume":"66","author":"Takeda","year":"2022","journal-title":"Microbiol. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41591-021-01347-0","article-title":"SARS-CoV-2 escaped natural immunity, raising questions about vaccines and therapies","volume":"27","author":"Andreano","year":"2021","journal-title":"Nat. Med."},{"key":"ref_7","first-page":"101212","article-title":"Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1\/S2 Site","volume":"23","author":"Jaimes","year":"2020","journal-title":"SSRN"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/s41586-022-04980-y","article-title":"BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection","volume":"608","author":"Cao","year":"2022","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113522","DOI":"10.1016\/j.biopha.2022.113522","article-title":"Omicron variant (B.1.1.529) and its sublineages: What do we know so far amid the emergence of recombinant variants of SARS-CoV-2?","volume":"154","author":"Dhawan","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1056\/NEJMc2206576","article-title":"Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5","volume":"387","author":"Hachmann","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1126\/science.abq3773","article-title":"Broadly neutralizing antibodies target the coronavirus fusion peptide","volume":"377","author":"Dacon","year":"2022","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1124\/pr.110.002733","article-title":"Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases","volume":"62","author":"Korkmaz","year":"2010","journal-title":"Pharmacol Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Akgun, E., Tuzuner, M.B., Sahin, B., Kilercik, M., Kulah, C., Cakiroglu, H.N., Serteser, M., Unsal, I., and Baykal, A.T. (2020). Proteins associated with neutrophil degranulation are upregulated in nasopharyngeal swabs from SARS-CoV-2 patients. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240012"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"AB59","DOI":"10.1016\/j.jaci.2021.12.223","article-title":"Cathepsin G in Patients with SARS-Cov-2 Infection of Various Degrees of Severity","volume":"149","author":"Beloglazov","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Goettig, P. (2016). Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17121969"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"629873","DOI":"10.3389\/fmolb.2021.629873","article-title":"Glycans of SARS-CoV-2 Spike Protein in Virus Infection and Antibody Production","volume":"8","author":"Zhao","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eabl5394","DOI":"10.1126\/sciadv.abl5394","article-title":"High-resolution profiling of MHC II peptide presentation capacity reveals SARS-CoV-2 CD4 T cell targets and mechanisms of immune escape","volume":"8","author":"Obermair","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7181","DOI":"10.1021\/acsomega.1c00363","article-title":"Neutrophil Elastase and Proteinase 3 Cleavage Sites Are Adjacent to the Polybasic Sequence within the Proteolytic Sensitive Activation Loop of the SARS-CoV-2 Spike Protein","volume":"6","author":"Mustafa","year":"2021","journal-title":"ACS Omega"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/nar\/gkab225","article-title":"Expasy, the Swiss Bioinformatics Resource Portal, as designed by its users","volume":"49","author":"Duvaud","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:27:17Z","timestamp":1760142437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":19,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["molecules27185817"],"URL":"https:\/\/doi.org\/10.3390\/molecules27185817","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}