Document Report Card

Basic Information

ID: ALA1921684

Journal: J Med Chem

Title: Targeting zymogen activation to control the matriptase-prostasin proteolytic cascade.

Authors: Xu Z, Chen YW, Battu A, Wilder P, Weber D, Yu W, Mackerell AD, Chen LM, Chai KX, Johnson MD, Lin CY.

Abstract: Membrane-associated serine protease matriptase has been implicated in human diseases and might be a drug target. In the present study, a novel class of matriptase inhibitors targeting zymogen activation is developed by a combination of the screening of compound library using a cell-based matriptase activation assay and a computer-aided search of commercially available analogues of a selected compound. Four structurally related compounds are identified that can inhibit matriptase activation with IC(50) at low micromolar concentration in both intact-cell and cell-free systems, suggesting that these inhibitors target the matriptase autoactivation machinery rather than the intracellular signaling pathways. These activation inhibitors can also inhibit prostasin activation, a downstream event that occurs in lockstep with matriptase activation. In contrast, the matriptase catalytic inhibitor CVS-3983 at a concentration 300-fold higher than its K(i) fails to inhibit activation of either protease. Our results suggest that inhibiting matriptase activation is an efficient way to control matriptase function.

CiteXplore: 21966950

DOI: 10.1021/jm200920s