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Inhibition of matriptase\u20102 is considered as an attractive strategy for the treatment of iron\u2010overload diseases, such as hemochromatosis and \u03b2\u2010thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds (<jats:bold>41<\/jats:bold>\u2013<jats:bold>45<\/jats:bold>) were identified and characterized kinetically as irreversible inhibitors of matriptase\u20102. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase\u20102 by binding to the S1 and S3\/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds <jats:bold>41<\/jats:bold>\u2013<jats:bold>45<\/jats:bold> were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound <jats:bold>45\u2009A<\/jats:bold>, with <jats:italic>S<\/jats:italic> configuration at the N\u2010terminal amino acid and <jats:italic>R<\/jats:italic> configuration at the phosphonate carbon atom, was the most potent matriptase\u20102 inactivator with a rate constant of inactivation of 2790\u2009<jats:sc>m<\/jats:sc><jats:sup>\u22121<\/jats:sup>\u2009s<jats:sup>\u22121<\/jats:sup> and abolished the activity of membrane\u2010bound matriptase\u20102 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe (<jats:bold>51\u2009A<\/jats:bold>) by insertion of a coumarin label is described. The in\u2010gel fluorescence detection of matriptase\u20102 was demonstrated by applying <jats:bold>51\u2009A<\/jats:bold> as the first activity\u2010based probe for this enzyme.<\/jats:p>","DOI":"10.1002\/chem.201600206","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T10:17:12Z","timestamp":1464085032000},"page":"8525-8535","source":"Crossref","is-referenced-by-count":22,"title":["Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity\u2010Based Probes of Matriptase\u20102"],"prefix":"10.1002","volume":"22","author":[{"given":"Daniela","family":"H\u00e4u\u00dfler","sequence":"first","affiliation":[{"name":"Pharmaceutical Institute Pharmaceutical Chemistry\u2005I University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Mangold","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute Pharmaceutical Chemistry\u2005I University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Furtmann","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute Pharmaceutical Chemistry\u2005I University of Bonn  An der Immenburg 4 53121 Bonn Germany"},{"name":"Department of Life Science Informatics, B-IT LIMES Program Unit Chemical Biology and Medicinal Chemistry University of Bonn  Dahlmannstrasse 2 53113 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annett","family":"Braune","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Microbiology German Institute of Human Nutrition Potsdam-Rehbruecke  Arthur-Scheunert-Allee 114\u2013116 14558 Nuthetal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Blaut","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Microbiology German Institute of Human Nutrition Potsdam-Rehbruecke  Arthur-Scheunert-Allee 114\u2013116 14558 Nuthetal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Bajorath","sequence":"additional","affiliation":[{"name":"Department of Life Science Informatics, B-IT LIMES Program Unit Chemical Biology and Medicinal Chemistry University of Bonn  Dahlmannstrasse 2 53113 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit","family":"Stirnberg","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute Pharmaceutical Chemistry\u2005I University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute Pharmaceutical Chemistry\u2005I University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,23]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R109.021006"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203007200"},{"key":"e_1_2_6_3_1","unstructured":"\u00a0"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.130"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157121"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-149773"},{"key":"e_1_2_6_7_1","unstructured":"\u00a0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68889"},{"key":"e_1_2_6_9_2","first-page":"1052","volume":"19","author":"Stirnberg M.","year":"2013","journal-title":"Curr. 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