title: Changing the selectivity profile - from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors.
abstract: The type II transmembrane serine protease matriptase is a potential target for anticancer therapy and might be involved in cartilage degradation in osteoarthritis or inflammatory skin disorders. Starting from previously described nonspecific thrombin and factor Xa inhibitors we have prepared new noncovalent substrate-analogs with superior potency against matriptase. The most suitable compound 35 (H-d-hTyr-Ala-4-amidinobenzylamide) binds to matriptase with an inhibition constant of 26 nM and has more than 10-fold reduced activity against thrombin and factor Xa. The crystal structure of inhibitor 35 was determined in the surrogate protease trypsin, the obtained complex was used to model the binding mode of inhibitor 35 in the active site of matriptase. The methylene insertion in d-hTyr and d-hPhe increases the flexibility of the P3 side chain compared to their d-Phe analogs, which enables an improved binding of these inhibitors in the well-defined S3/4 pocket of matriptase. Inhibitor 35 can be used for further biochemical studies with matriptase.
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Maiwald
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Maya
authors.initials: M
authors.lastname: Hammami
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wagner
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.affiliation: a Department of Pharmacy , Institute of Pharmaceutical Chemistry, Philipps University , Marburg , Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase; D013917:Thrombin; D015951:Factor Xa
keywords: Benzamidines; X-ray structure; matriptase; protease inhibition; trypsin