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- Title
Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity-Based Probes of Matriptase-2.
- Authors
Häußler, Daniela; Mangold, Martin; Furtmann, Norbert; Braune, Annett; Blaut, Michael; Bajorath, Jürgen; Stirnberg, Marit; Gütschow, Michael
- Abstract
Matriptase-2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase-2 is considered as an attractive strategy for the treatment of iron-overload diseases, such as hemochromatosis and β-thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds ( 41- 45) were identified and characterized kinetically as irreversible inhibitors of matriptase-2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase-2 by binding to the S1 and S3/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds 41- 45 were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound 45 A, with S configuration at the N-terminal amino acid and R configuration at the phosphonate carbon atom, was the most potent matriptase-2 inactivator with a rate constant of inactivation of 2790 m−1 s−1 and abolished the activity of membrane-bound matriptase-2 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe ( 51 A) by insertion of a coumarin label is described. The in-gel fluorescence detection of matriptase-2 was demonstrated by applying 51 A as the first activity-based probe for this enzyme.
- Subjects
MATRIPTASE; SERINE proteinase inhibitors; HOMEOSTASIS; FLUORESCENT probes; PEPTIDOMIMETICS
- Publication
Chemistry - A European Journal, 2016, Vol 22, Issue 25, p8525
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201600206