| Project/Area Number |
07557162
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | The Kitasato Institute |
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Principal Investigator |
OHMURA Satoshi The Kitasato Institute, Researach Center for Biological Function, President and Professor, 生物機能研究所, 所長 (90050426)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Hiroyuki The University of Tokyo Graduate School of Pharmaceutical Sciences, Associate Pr, 大学院・薬学系研究科, 助教授 (40167987)
MASUMA Rokuro The Kitasato Institute, Researach Center for Biological Function, Chief Research, 生物機能研究所, 室長 (90219353)
MORIKAWA Yuko The Kitasato Institute, Researach Center for Basic Research, Chief Researcher, 基礎研究所, 室長 (20191017)
INOKOSHI Junji Kitasato University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 講師 (30151640)
TOMODA Hiroshi The KItasato Institute, Researach Center for Biological Function, Chief Research, 生物機能研究所, 副所長 (70164043)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1996: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | Myristoylation / Farnesyltransferase / HIV Gag protein / Triacsin / Acly-Coa synthetase / Inhibitor / Ras protein / Andrastin / 抗エイズ薬 / 抗癌剤 / 脂質修飾蛋白質 / アシル化 / 抗エイズ剤 |
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| Research Abstract |
Many cellular proteins are modified with lipids such as acyl(palmitoyl or myristoly)and/or prenly(farnesly or geranylgeranyl)residues. In this researach project, the biochemical functions of lipid-modified proteins were studied and searaach for microbial inhibitors of their formation wes carried out as a new approach for anticancer or antiviral agents.
HIV Gag protein is myrisstoylataed at the N-terminal glycine residue, which plays an important role in virus particlebdding. The myristoylation levels were controlled to investigate the effect on the particle budding by using the specifiv acyl-CoA synthetase inhibitor triacsin previousy discovered by our group. We showed that the inhibition of Gag myristoylation by triacsin follows dose-dependent kinetics but that the particle budding exhibits sudden shutoff kinetics, suggesting that only a relatively small proportion of total Gag molecules need to be myristoylated for efficient budding and indicating that total inhibition of myristoylation will be required for effective anti-HIV therapy.
Oncogene product Ras proteins are posttranslationally farnesylated at the cysteine residue near the C-terminus, in which protein farnesyltransferase(PFTase)is involved. PFTase is expected as a novel target of inhibition since the inhibition causes altering membrane localization and blocking activation of Ras proteins. An efficient screening system was conducted by utilizing Saccharomyces cerevisiae, resulting in discovery of two series of new PTFase inhibitors, andrastins produced by Penicillium sp.FO-3929 and kurasoins by Paecilomyces sp.FO-3684. The structure elucidation including stereochemistries, biosynthesis of andrastin and total sylnthesis of kurasoin were studied. Their inhibitory activity against PFTase (IC_<50>) was 10-60muM.
It still remains to be investigated whether or not these compounds inhibit PFTase in cells and show in fvivo anticancer activity.
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