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Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Meprin \u03b2 is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin \u03b2 expression and activity was observed in several pathological conditions such as Alzheimer\u2019s disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin \u03b2 could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin \u03b2 inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin \u03b2 propeptide serves as highly specific inhibitor for the protease (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.35 \u00b5M), while other related metalloproteases such as meprin \u03b1 and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.68 \u00b5M). In cell-based experiments, treatment with the propeptide resulted in diminished meprin \u03b2 activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin \u03b2 activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin \u03b2 represent highly specific inhibitors with potential for therapeutic application.\n                  <\/jats:p>","DOI":"10.1007\/s00018-026-06361-4","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T07:29:23Z","timestamp":1784791763000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Meprin \u03b2 is specifically inhibited by its cognate synthetic propeptide"],"prefix":"10.1007","volume":"83","author":[{"given":"Fred","family":"Armbrust","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Bruhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira","family":"Bickenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Steen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapir","family":"Shcoory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Afratis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele","family":"Korn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagen","family":"K\u00f6rschgen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Moali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus U.","family":"Pietrzik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irit","family":"Sagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5100-9916","authenticated-orcid":false,"given":"Christoph","family":"Becker-Pauly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"6361_CR1","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1042\/BJ20121751","volume":"450","author":"C Broder","year":"2013","unstructured":"Broder C, Becker-Pauly C (2013) The metalloproteases meprin \u03b1 and meprin \u03b2: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. 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