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Aminophosphonates as Novel Activity-Based Probes for Matriptase-2
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1  Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

Activity-based probes form covalent bonds with active enzymes and can be utilized to profile enzyme activities in vivo, to identify target enzymes and to characterize their function. They have a reactive head group that covalently binds to the target, a tag that allows detection (e.g. a fluorophore) and a linker to connect both.[1]

Matriptase-2 is a transmembrane, multi-domain serine protease with primary substrate specificity for arginine in P1 position, which plays a key role in the human iron homeostasis.[2] Our design of activity-based probes for matriptase-2 is based on linker-connected bis-benzguanidines.[3] The two benzguanidine units interact as arginine mimetics with the S1 and the upper part of the S3/S4 pocket, respectively, and direct the inhibitor to the active site of the target enzyme.[2] An amino acid was introduced as a linker, which bears the coumarin fluorophore. Moreover, an incorporated phosphonate allows for a covalent interaction with the active-site serine.[4] The resulting irreversible mode of action was demonstrated, leading to an enzyme inactivation and, simultaneously, to a fluorescence labeling of matriptase-2.

Herein, we present the preparation of coumarin-functionalized amino acids and the subsequent linear synthetic approach to coumarin-labeled bis-benzguanidines as activity-based probes for matriptase-2. Spectral properties and kinetic parameters for the reaction with matriptase-2 are reported.



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  2. Stirnberg, M.; Gütschow, M. Curr. Pharm. Des. 2013, 19, 1052-1061.
  3. Dosa, S.; Stirnberg, M.; Lülsdorff, V.; Häußler, D.; Maurer, E.; Gütschow, M. Bioorg. Med. Chem. 2012, 20, 6489-6505.
  4. Scienczyk, M.; Oleksyszyn, J. Curr. Med. Chem. 2009, 16, 1673-1687.
Keywords: activity-based probe, guanidine, matriptase-2, phosphonate