Development of novel therapeutic agents against African sleeping sickness targeted for GMP reductase.
| Project/Area Number |
25660231
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Veterinary medical science
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| Research Institution | Osaka Prefecture University |
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Principal Investigator |
Inui Takashi 大阪府立大学, 生命環境科学研究科(系), 教授 (80352912)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIBASHI Osamu 大阪府立大学, 生命環境科学研究科, 准教授 (70293214)
NISHIMURA Shigenori 大阪府立大学, 生命環境科学研究科, 助教 (90244665)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 人獣共通感染症 / 寄生虫 / 核酸合成系酵素 / 酵素反応速度論的解析 / 医薬候補化合物 / X線結晶構造解析 / 酵素 / 薬剤反応性 / 獣医学 / 有機合成 |
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| Outline of Final Research Achievements |
We characterized the steady-state kinetics of Trypanosoma brucei (T. brucei) GMP reductase (TbGMPR). TbGMPR but no enzymes of the host mammals was inhibited in the presence of a purine nucleotide analog ribavirin 5’-monophosphate (RMP) with a Ki value of 4.46 μM. RMP and its precursor ribavirin showed anti-parasitic effect on bloodstream forms of T. brucei in culture, and the IC50 of each compound was ranged around 25 μM. We further prepared a mutant enzyme (TbGMPR-d) lacking cystathionine β-synthase domain, which is absent in mammalian GMPRs, to determine its structure by X-ray crystallography. The structure of TbGMPR-d was resolved at 2.36Å and found to have a TIM barrel structure commonly observed in GMPRs of other organisms. However, in quaternary structure, TbGMPR-d showed a different subunit orientation as compared to that of human GMPR2. The enzyme assay revealed that the activity of TbGMPR-d was apparently lowered than the wild-type enzyme.
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Report
(4 results)
Research Products
(81 results)
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[Journal Article] Development of pH-independent drug release formulation using lipocalin-type prostaglandin D synthase.2016
Author(s)
Mizoguchi, M., Nakatsuji, M., Takano, J., Ishibashi, O., Wada, K., Inui, T.
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Journal Title
J. Pharm. Sci.
Volume: 掲載確定
Issue: 9
Pages: 1-8
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Novel Characteristics of Guanosine 5’-monophosphate 1 Reductase in Pathogenic2 Protozoa Trypanosoma brucei Distinct from Host Animal.2016
Author(s)
T. Bessho, T. Okada, C. Kimura, T. Shinohara, A. Tomiyama, A. Imamura, M. Kuwamura, K. Nishimura, K. Fujimori, .S. Shuto, O. Ishibashi, B. K. Kubata, T. Inui
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Journal Title
PLoS Negl. Trop. Dis
Volume: 10
Issue: 1
Pages: e0004339-e0004339
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Nuclear-translocated glyceraldehyde-3-phosphate dehydrogenase promotes poly(ADP-ribose) polymerase-1 activation during oxidative/nitrosative stress in stroke.2015
Author(s)
Nakajima H, Kubo T, Ihara H, Hikida T, Danjo T, Nakatsuji M, Shahani N, Itakura M, Ono Y, Azuma Y, Inui T, Kamiya A, Sawa A, Takeuchi T
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Journal Title
J. Biol. Chem.
Volume: VOL. 290
Issue: 23
Pages: 14493-14503
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38.2015
Author(s)
Nakatsuji, M., Inoue, H., Kohno, M., Saito, M., Tsuge, S., Shimizu, S., Ishida, A., Ishibashi, O., Inui, T.
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Journal Title
PLoS ONE
Volume: 10(11)
Issue: 11
Pages: e0142206-e0142206
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.2015
Author(s)
Itakura, M., Nakajima, H., Kubo, T., Semi, Y., Kume, S., Higashida, S., Kaneshige, A., Kuwamura, M., Harada, N., Kita, A., Azuma, Y. T., Yamaji, R., Inui, T., Takeuchi, T.
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Journal Title
J. Biol. Chem.
Volume: 290
Issue: 43
Pages: 26072-26087
DOI
Related Report
Peer Reviewed
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[Journal Article] A Toxin Isolated from Sarcocystis fayeri in Raw Horsemeat May Be Responsible for Food Poisoning2014
Author(s)
Kamata, Y., Saito, M.,Irikura, D.,Yahata,Y.,Ohnishi, T., Bessho,T.,Inui,T.,Watanabe,M.,Konoshi,Y.,
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Journal Title
Journal of Food Protection
Volume: 77
Issue: 5
Pages: 814-819
DOI
Related Report
Peer Reviewed
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[Journal Article] Characterization of the novel Trypanosoma brucei inosine 5'-monophosphate dehydrogenase.2013
Author(s)
Bessho T, Morii S, Kusumoto T, Shinohara T, Noda M, Uchiyama S, Shuto S, Nishimura S, Djikeng A, Duszenko M, Martin SK, Inui T, Kubata KB.
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Journal Title
Parasitology
Volume: 140
Issue: 6
Pages: 735-745
DOI
Related Report
Peer Reviewed
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