Inhibitors of autoactivation of plasma hyaluronan-binding protein (factor 7 activating protease)

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  • Yamamoto Eisaku
    Department of Applied Biological Science, Tokyo Noko University
  • Nishimura Naoko
    Department of Applied Biological Science, Tokyo Noko University
  • Okada Ken
    Department of Applied Biological Science, Tokyo Noko University
  • Sekido Chikako
    Department of Applied Biological Science, Tokyo Noko University
  • Yamamichi Shingo
    Department of Applied Biological Science, Tokyo Noko University
  • Hasumi Keiji
    Department of Applied Biological Science, Tokyo Noko University

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タイトル別名
  • Inhibitors of Autoactivation of Plasma Hyaluronan-Binding Protein (Factor VII Activating Protease)

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説明

Plasma hyaluronan-binding protein (PHBP), a serine protease that can activate coagulation factor VII and prourokinase, circulates in a single-chain form (pro-PHBP) and autoproteolytically converts to an active two-chain form with the aid of an effector such as spermidine and heparin. It has been postulated that PHBP plays roles in regulating inflammation, vascular function, fibrosis and atherosclerosis. From the comprehensive screening of natural sources for inhibitors of spermidine-induced pro-PHBP autoactivation, we identified several compounds with a polyphenol feature. Of these inhibitors, tannic acid (IC50=0.020 μM), delphinidin (IC50=0.079 μM), hamamelitannin (IC50=0.19 μM), (−)-epicatechin gallate (IC50=0.24 μM), and 3,5-di-O-caffeoylquinic acid (IC50=1.0 μM) were potent and selective, and did not inhibit heparin-induced pro-PHBP autoactivation and the active form of PHBP at concentrations 100 times higher than the respective IC50 values. From evaluation of the activities of related compounds, it has been suggested that a compound with multiple aromatic rings with plural phenolic hydroxyl substituents exhibits potent activity. The inhibitory actions of delphinidin, hamamelitannin, (−)-epicatechin gallate and 3,5-di-O-caffeoylquinic acid were attenuated by catechol, a minimum polyphenol unit. Thus, it is likely that pro-PHBP binds these potent inhibitors through its site(s) that recognize a catechol-like structure. Our results would facilitate understanding of the molecular mechanism of pro-PHBP autoactivation and rational design of a compound for suppressing unregulated pro-PHBP activation.

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