New synthetic inhibitors of C1r̄, C1 esterase, thrombin, plasmin, kallikrein and trypsin

Fujii, Satoshi; Hitomi, Yuji

doi:10.1016/0005-2744(81)90023-1

Cited by 283 publications

(172 citation statements)

References 16 publications

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“…FM3A cells (5x10') were suspended in 0.8 ml buffer A containing 10 mM Tris/HCl, pH 7.5, 1 mM dithiothreitol, 20% glycerol, 1 mM EDTA and 20 pM 6-amino-2-naphthyl-4-guanidinobenzoate dihydrochloride, a strong proteinase inhibitor [16]. They were frozen, thawed, then homogenized with a Teflon homogenizer.…”

Section: Enzyme Assaysmentioning

confidence: 99%

Correlation between the inhibition of cell growth by bis(ethyl)polyamine analogues and the decrease in the function of mitochondria

Suzuki

Kashiwagi

et al. 1994

European Journal of Biochemistry

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The antiproliferating effect of nine kinds of bis(ethy1)polyamine analogues [three kinds each of bis(ethyl)triamine, bis(ethy1)tetraamine and bis(ethy1)pentaaminel was compared using FM3 A cells.The inhibitory effect was in the order BE4444 > BE3443 > BE4334ZBE444 > BE343 > BE333 > BE44 > BE34 > BE33. Our results indicate that not only polyamine deficiency but also the accumulation of polyamine analogues is involved in the inhibition of cell growth. Accumulation of bis(ethy1)polyamine analogues caused the inhibition of protein synthesis and the decrease in the ATP content. The protein synthetic system in mitochondria was more strongly inhibited by bis(ethy1)polyamine analogues than that in the cytoplasm. Under conditions such that cytoplasmic protein synthesis was inhibited by 50% by bis(ethy1)polyamine analogues, mitochondrial protein synthesis was almost completely inhibited. Mitochondria1 Ile-tRNA formation was inhibited by bis(ethy1)polyamine analogues at the concentrations that cytoplasmic Ile-tRNA formation was stimulated. This may be one of the reasons for the selective inhibition of mitochondrial protein synthesis. This inhibition was followed by the decrease in ATP content, swelling of mitochondria and depletion of mitochondrial DNA. These results suggest that the early event of metabolic change caused by bis(ethy1)polyamine analogues in cells is the inhibition of protein synthesis, especially of mitochondrial protein synthesis.Since the polyamines putrescine, spermidine and spermine are essential for the maintenance of eukaryotic cell proliferation [ 11, inhibitors of polyamine biosynthesis to deplete cellular polyamines have been developed as antiproliferative reagents [2, 31. Bis(ethy1)polyamine analogues have also been developed as antiproliferative reagents [4, 51. These reagents can not only negatively regulate the synthesis of omithine decarboxylase (OmDC) and S-adenosylmethionine decarboxylase (AdoMetDC) [6], but can also induce spermidinekpermine A"-acetyltransferase (SSAT) activity [7, 81. Thus, the analogues can deplete intracellular polyamines almost completely, and they are thought to inhibit cell growth through this process. We found that A", W'-bis(ethyl)spermine (BE343) can substitute for the functions of spermine in various aspects and accumulate in cells at a concentration fivefold that of spermine in control cells [9, lo], and suggested that not only polyamine deficiency but also the accumulation of BE343 may be involved in the inhibition of cell growth [lo]. Recently, it has been reported that the inhibition of cell growth by BE343 correlated with the intracellular acCorrespondence to K. Igarashi, Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, Japan 263Fax: +81 43 290 2900. Abbreviations. OmDC, ornithine decarboxylase; AdoMetDC, S-adenosylmethionine decarboxylase; SSAT, spermidinehpermine W-acetyltransferase.Enzymes. Ornithine decarboxylase (EC 4.1.1.17) ; S-adenosylmethionine decarboxylase (EC 4.1.1.50) ; spermidinehpermine W-acetyltransferase...

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Section: Enzyme Assaysmentioning

confidence: 99%

Correlation between the inhibition of cell growth by bis(ethyl)polyamine analogues and the decrease in the function of mitochondria

Suzuki

Kashiwagi

et al. 1994

European Journal of Biochemistry

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“…The proteinase inhibitors [3,6,81 and various proteinases have been detected in seminal plasma, including plasminogen/plasmin (EC 3.4.2 1.7) [9], tissue plasminogen activator (t-PA, EC 3.4.21.68) [2,16,181, tissue kallikrein (EC 3.4.21.35) [7,131, and other chymotrypsin (EC 3.4.21.1)-like [17] and trypsin (EC 3.4.21.4)-like basic arginine amidases [4, lo]. The physiological roles and significance of these proteinases and the proteinase inhibitors are currently under intense examination.…”

mentioning

confidence: 99%

Fibrinogen-Like Substance and Thrombin-Like Enzyme in Human Seminal Plasma: Coagulation System of Human Semen

Park¹,

Yoshimura²,

Nozawa³

et al. 1997

Archives of Andrology

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“…Nafamostat mesilate (NM), (6-amidinonaphthalen-2-yl 4-guanidinobenzoate bis (methanesulfonate)) is a synthetic serine protease inhibitor (Fujii and Hitomi 1981). It inhibits a broad range of proteases and was shown to suppress the leakage of CatB from lysosomes in rat models of acute pancreatitis (Manabe et al 1992).…”

Section: Introductionmentioning

confidence: 99%

A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease

Nishimura

Yamaya

2015

Tohoku J. Exp. Med.

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Ebola virus disease (EVD) has been a great concern worldwide because of its high mortality. EVD usually manifests with fever, diarrhea and vomiting, as well as disseminated intravascular coagulation (DIC). To date, there is neither a licensed Ebola vaccine nor a promising therapeutic agent, although clinical trials are ongoing. For replication inside the cell, Ebola virus (EBOV) must undergo the proteolytic processing of its surface glycoprotein in the endosome by proteases including cathepsin B (CatB), followed by the fusion of the viral membrane and host endosome. Thus, the proteases have been considered as potential targets for drugs against EVD. However, no protease inhibitor has been presented as effective clinical drug against it. A synthetic serine protease inhibitor, nafamostat mesilate (NM), reduced the release of CatB from the rat pancreas. Furthermore, it has anticoagulant activities, such as inhibition of the factor VIIa complex, and has been used for treating DIC in Japan. Thus, NM could be considered as a drug candidate for the treatment of DIC induced by EBOV infection, as well as for the possible CatB-related antiviral action. Moreover, the drug has a history of large-scale production and clinical use, and the issues of safety and logistics might have been cleared. We advocate in vitro and in vivo experiments using active EBOV to examine the activities of NM against the infection and the DIC induced by the infection. In addition, we suggest trials for comparison among anti-DIC drugs including the NM in EVD patients, in parallel with the experiments.

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New synthetic inhibitors of C1r̄, C1 esterase, thrombin, plasmin, kallikrein and trypsin

Cited by 283 publications

References 16 publications

Correlation between the inhibition of cell growth by bis(ethyl)polyamine analogues and the decrease in the function of mitochondria

Correlation between the inhibition of cell growth by bis(ethyl)polyamine analogues and the decrease in the function of mitochondria

Fibrinogen-Like Substance and Thrombin-Like Enzyme in Human Seminal Plasma: Coagulation System of Human Semen

A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease

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