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Due to the emergence of antiviral drug\u2010resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR\u2010Kbt (<jats:bold>IN\u20101<\/jats:bold>, aka N\u20100100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses. We also introduced modifications of the peptidomimetics N\u2010terminal groups, leading to significant improvements (from \u03bcM to nM, 60 times more potent than <jats:bold>IN\u20101<\/jats:bold>) in their ability to inhibit the replication of influenza H1N1 virus in the Calu\u20103\u2005cell line derived from human lungs. The selectivity towards other proteases has been evaluated and explained using molecular modeling with a crystal structure recently obtained by our group. By targeting host cell TTSPs as a therapeutic approach, it may be possible to overcome the high mutational rate of influenza viruses and consequently prevent potential drug resistance.<\/jats:p>","DOI":"10.1002\/cmdc.202300458","type":"journal-article","created":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T10:25:06Z","timestamp":1697883906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Optimization of Ketobenzothiazole\u2010Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication"],"prefix":"10.1002","volume":"19","author":[{"given":"\u00c9lo\u00efc","family":"Colombo","sequence":"first","affiliation":[{"name":"Department of Pharmacology-Physiology Faculty of Medicine and Health Sciences and Institut de Pharmacologie de Sherbrooke Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5081-5564","authenticated-orcid":false,"given":"Antoine","family":"D\u00e9silets","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Physiology Faculty of Medicine and Health Sciences and Institut de Pharmacologie de Sherbrooke Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malihe","family":"Hassanzadeh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Physiology Faculty of Medicine and Health Sciences and Institut de Pharmacologie de Sherbrooke Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-5528","authenticated-orcid":false,"given":"Gabriel","family":"Lemieux","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Physiology Faculty of Medicine and Health Sciences and Institut de Pharmacologie de Sherbrooke Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Marois","sequence":"additional","affiliation":[{"name":"Department of Medicine Faculty of Medicine and Health Sciences Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"},{"name":"Current address: Department of Biology Faculty of Sciences Universit\u00e9 de Sherbrooke  Sherbrooke J1K 2R1 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic","family":"Cliche","sequence":"additional","affiliation":[{"name":"Department of Medicine Faculty of Medicine and Health Sciences Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7282-4971","authenticated-orcid":false,"given":"Julien A.","family":"Delbrouck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Physiology Faculty of Medicine and Health Sciences and Institut de Pharmacologie de Sherbrooke Universit\u00e9 de Sherbrooke  Sherbrooke J1H 5N4 Qu\u00e9bec Canada"},{"name":"Current address: Xenon Pharmaceuticals Inc.  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