DEVELOPMENT OF CHEMOTHERAPY FOR AFRICAN TRYPANOSOMIASIS USING ASCOFURANONE
| Project/Area Number |
17390122
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Parasitology (including Sanitary zoology)
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| Research Institution | Nagoya City University |
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Principal Investigator |
YABU Yoshisada Nagoya City University, Graduate School of Medical Sciences, Assistant Professor (70080083)
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| Co-Investigator(Kenkyū-buntansha) |
KITA Kiyoshi The University of Tokyo, Graduate School of Medicine, Professor (90134444)
SAIMOTO Hiroyuki Tottori University, School of Technology, Professor (20186977)
SUZUKI Takashi Nagoya City University, Graduate School of Medical Sciences, Research Associate (70305530)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥11,460,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥660,000)
Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥4,400,000 (Direct Cost: ¥4,400,000)
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| Keywords | Rhodesian sleeping sickness / Cyanide insensitive alternative oxidase / Ascofuranone / Mice / Derivatives / Chemotherapy / ローデシア睡眼病 / アフリカトリパノソーマ / ヤギ / 寄生虫 / 血流 / 原虫 / 治療薬 / 組み換え酵素 / アフリカ睡眠病 |
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| Research Abstract |
(1) The chemotherapeutic effect of ascofuranone on Rhodesian sleeping sickness in mice: Experimental treatment by ascofuranone was started 5 days after infection with 10^6/mouse with Trypanosoma b. rhodesiense in mice. Infected mice were administered with 100 mg/kg ascofuranone for 4, 6 and 8 consecutive days intraperitoneally. In this experiment, all treated mice showed relapse. Experimental treatment was modified to combination administration with ascofuranone and glycerol for 3, 5 and 7 consecutive days. Infected mice were administered with 100 mg/kg ascofuranone intraperitoneally and after 1 hr same mice were given 3 g/kg glycerol. In this experiment, all treated mice also showed reappearance of parasites. So experiment was changed again. Infected mice were administered 100 mg/kg ascofuranone and glycerol was also given 2 times after 1 h every 2 hrs. This treatment was done 1, 3 and 5 consecutive days. In this experiment, infected mice administered ascofuranone and twice of glycerol for 5 consecutive days were cured while other treated mice relapsed.
(2) Synthesis of ascofuranone derivatives, correlation between conformation and anti-trypanosomal activity: Ascofuranone derivatives of many types of side chain, replaced of franone ring with another active site, and removing of franone ring were synthesized and determined the growth inhibition of cultured trypanosomes. In this experiment, 3 types of derivatives showed growth inhibition effectively.
(3) Analysis of inhibitory mechanisms of ascofuranone against recombinant enzyme: AOX (alternative oxidase) gene was cloned from Trypanosoma b. rhodesiense cDNA and expressed recombinant enzyme in E. coli. Inhibitory mechanism of ascofuranone against expressed recombinant enzyme was analyzed. In this experiment ascofuranone showed competitive inhibition against recombinant enzyme.
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Trypanosoma bruceivacuolar protein sorting 41 (VPS41) is required for intracellular iron utilization and maintenance of normal cellular morphology2007
Author(s)
Lu, S., Suzuki, T., Iizuka, N., Ohshima, S., Yabu, Y., Suzuki, M., Wen, L., Ohta, N
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Journal Title
Parasitology 134
Pages: 1639-1647
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Alternative oxidase (AOX) genes of African trypanosomes: Phylogeny and evolution of AOX and plastid terminal oxidase families.2005
Author(s)
Suzuki, Hashimoto, Yabu, Majiwa, Ohshima, Suzuki, Lu, Hato, Kido, Sakamoto, Nakamura, Kita, Ohta
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Journal Title
Journal of Eukaryotic Microbiology 52
Pages: 374-381
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[Journal Article] Mutational analysis of the Trypanosoma vivax alternative oxidase: The E(X)_6Y motif is conserved in both mitochondrial alternative oxidase and plastid terminal oxidase and is indispensable for enzyme activity.2005
Author(s)
Nakamura, Sakamoto, Kido, Fujimoto, Suzuki, Suzuki, Yabu, Ohta, Tsuda, Onuma, Kita
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Journal Title
Biochemical and Biophysical Research Communications 334
Pages: 593-600
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[Presentation] Target of glycerol in ascofuranone/glycerol in vitro trypanocidal effect to African trvoanosomes2007
Author(s)
Fujioka, S., Nakamura, K., Kido, Y., Sakamoto, K., Haga, Y., Saimoto, H., Suzuki, T., Yabu, Y., Kita, K
Organizer
80th annual meeting of Biochemistry
Place of Presentation
Japan
Year and Date
2007-12-14
Description
「研究成果報告書概要(欧文)」より
Related Report
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