title: Targeting zymogen activation to control the matriptase-prostasin proteolytic cascade.
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.
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Xu
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Aruna
authors.initials: A
authors.lastname: Battu
authors.forename: Paul
authors.initials: P
authors.lastname: Wilder
authors.forename: David
authors.initials: D
authors.lastname: Weber
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Mackerell
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Chen
authors.forename: Karl X
authors.initials: KX
authors.lastname: Chai
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
mesh_terms: D002460:Cell Line; D002474:Cell-Free System; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D057166:High-Throughput Screening Assays; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D059748:Proteolysis; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099271:Prostasin
chemical_list: D004792:Enzyme Precursors; D009842:Oligopeptides; D011758:Pyrroles; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099271:Prostasin; C493012:CVS-3983; C485595:matriptase