title: Design and synthesis of potent, selective inhibitors of matriptase.
abstract: Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Eloïc
authors.initials: E
authors.lastname: Colombo
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Désilets
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Duchêne
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Félix
authors.initials: F
authors.lastname: Chagnon
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Rafael
authors.initials: R
authors.lastname: Najmanovich
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: Department of Pharmacology and Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke PQ, J1H5N4, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Marsault
keywords: matriptase; slow tight-binding inhibitor; type II transmembrane serine protease