{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:19:17Z","timestamp":1780604357099,"version":"3.54.1"},"reference-count":20,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Volkswagen Foundation","award":["9A894"],"award-info":[{"award-number":["9A894"]}]},{"name":"Open Access Publication Fund of the University of W\u00fcrzburg","award":["9A894"],"award-info":[{"award-number":["9A894"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 \u00b5M suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.<\/jats:p>","DOI":"10.3390\/ijms24043972","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T03:32:30Z","timestamp":1676518350000},"page":"3972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cell Type-Specific Anti-Viral Effects of Novel SARS-CoV-2 Main Protease Inhibitors"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2974-6290","authenticated-orcid":false,"given":"Nina","family":"Geiger","sequence":"first","affiliation":[{"name":"Institute for Virology and Immunobiology, University of W\u00fcrzburg, Versbacher Strasse 7, 97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Diesendorf","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of W\u00fcrzburg, Versbacher Strasse 7, 97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Roll","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of W\u00fcrzburg, Versbacher Strasse 7, 97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Maria","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of W\u00fcrzburg, Versbacher Strasse 7, 97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Obernolte","sequence":"additional","affiliation":[{"name":"Member of DZL, BREATH and iCAIR, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-4527","authenticated-orcid":false,"given":"Katherina","family":"Sewald","sequence":"additional","affiliation":[{"name":"Member of DZL, BREATH and iCAIR, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5986-348X","authenticated-orcid":false,"given":"Julian","family":"Breidenbach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5575-8896","authenticated-orcid":false,"given":"Thanigaimalai","family":"Pillaiyar","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7897","authenticated-orcid":false,"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0013-6624","authenticated-orcid":false,"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1908-4091","authenticated-orcid":false,"given":"Jochen","family":"Bodem","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of W\u00fcrzburg, Versbacher Strasse 7, 97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19 in real time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","unstructured":"Kemnic, T.R., and Gulick, P.G. (2022). StatPearls, StatPearls Publishing, Treasure Island."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41575-022-00608-8","article-title":"Breakthroughs in hepatitis C research: From discovery to cure","volume":"19","author":"Manns","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nm1777","article-title":"Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs","volume":"14","author":"Shen","year":"2008","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10423","DOI":"10.1002\/anie.202016961","article-title":"Targeting the main protease of SARS-CoV-2: From the establishment of high throughput screening to the design of tailored inhibitors","volume":"60","author":"Breidenbach","year":"2021","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Citarella, A., Scala, A., Piperno, A., and Micale, N. (2021). SARS-CoV-2 M(pro): A potential target for peptidomimetics and small-molecule inhibitors. Biomolecules, 11.","DOI":"10.3390\/biom11040607"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1021\/jm061425k","article-title":"Design, synthesis, and evaluation of inhibitors for severe acute respiratory syndrome 3C-like protease based on phthalhydrazide ketones or heteroaromatic esters","volume":"50","author":"Zhang","year":"2007","journal-title":"J. Med. Chem"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5684","DOI":"10.1016\/j.bmcl.2008.08.082","article-title":"Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors","volume":"18","author":"Ghosh","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9376","DOI":"10.1021\/acs.jmedchem.2c00636","article-title":"Small-molecule thioesters as SARS-CoV-2 main protease inhibitors: Enzyme inhibition, structure-activity relationships, antiviral activity, and X-ray structure determination","volume":"65","author":"Pillaiyar","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41589-020-00689-z","article-title":"SARS-CoV-2 M(pro) inhibitors and activity-based probes for patient-sample imaging","volume":"17","author":"Rut","year":"2021","journal-title":"Nat. Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11419","DOI":"10.1002\/chem.201101350","article-title":"Facing the gem-dialkyl effect in enzyme inhibitor design: Preparation of homocycloleucine-based azadipeptide nitriles","volume":"17","author":"Frizler","year":"2011","journal-title":"Chemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1021\/acsinfecdis.0c00644","article-title":"Azanitrile inhibitors of the SmCB1 protease target are lethal to schistosoma mansoni: Structural and mechanistic insights into chemotype reactivity","volume":"7","author":"Jilkova","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/s41586-020-2575-3","article-title":"Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2","volume":"585","author":"Hoffmann","year":"2020","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5890","DOI":"10.1038\/s41598-021-85049-0","article-title":"The serotonin reuptake inhibitor fluoxetine inhibits SARS-CoV-2 in human lung tissue","volume":"11","author":"Zimniak","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"801870","DOI":"10.3389\/fbioe.2022.801870","article-title":"Selection and validation of siRNAs preventing uptake and replication of SARS-CoV-2","volume":"10","author":"Friedrich","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Geiger, N., Kersting, L., Schlegel, J., Stelz, L., Fahr, S., Diesendorf, V., Roll, V., Sostmann, M., K\u00f6nig, E.M., and Reinhard, S. (2022). The acid ceramidase is a SARS-CoV-2 host factor. Cells, 11.","DOI":"10.3390\/cells11162532"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Geiger, N., K\u00f6nig, E.M., Oberwinkler, H., Roll, V., Diesendorf, V., F\u00e4hr, S., Obernolte, H., Sewald, K., Wronski, S., and Steinke, M. (2022). Acetylsalicylic acid and salicylic acid inhibit SARS-CoV-2 replication in precision-cut lung slices. Vaccines, 10.","DOI":"10.1101\/2022.08.09.503270"},{"key":"ref_18","first-page":"3333","article-title":"Disulfiram blocked cell entry of SARS-CoV-2 via inhibiting the interaction of spike protein and ACE2","volume":"12","author":"Chen","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e01833-20","DOI":"10.1128\/mBio.01833-20","article-title":"GRL-0920, an indole chloropyridinyl ester, completely blocks SARS-CoV-2 infection","volume":"11","author":"Hattori","year":"2020","journal-title":"mBio"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41564-020-00846-z","article-title":"The SARS-CoV-2 RNA-protein interactome in infected human cells","volume":"6","author":"Schmidt","year":"2021","journal-title":"Nat. Microbiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3972\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:31Z","timestamp":1760121451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":20,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043972"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043972","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]}}}