title: Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12.
abstract: We describe a prodrug concept in which the target enzyme MMP12 produces its own inhibitor in a two-step activation procedure. By using an MMP12-specific peptide sequence and a known sulfonamide drug integrated in the backbone, the active inhibitor is released upon enzyme cleavage. In in vitro experiments, we present proof of concept that the activation proceeds with useful kinetics. The approach is highly selective over the closely related MMP8. If applied in vivo in the future, these prodrugs might release the active entity in a highly specific manner only at such sites where enzyme activity resides.
authors.affiliation: Cell Biology and Biophysics Unit, EMBL , Meyerhofstraße 1, 69117 Heidelberg, Germany ; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and EMBL , Otto-Meyerhof-Centre, Im Neuenheimer Feld, 69124 Heidelberg, Germany.
authors.forename: Amanda
authors.initials: A
authors.lastname: Cobos-Correa
authors.affiliation: Cell Biology and Biophysics Unit, EMBL , Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stein
authors.affiliation: Cell Biology and Biophysics Unit, EMBL , Meyerhofstraße 1, 69117 Heidelberg, Germany ; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and EMBL , Otto-Meyerhof-Centre, Im Neuenheimer Feld, 69124 Heidelberg, Germany ; Translational Lung Research Center Heidelberg (TLRC) , Member of the German Center for Lung Research.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
keywords: MMP; inflammation; inhibitors; prodrug; proteases