Structure-activity relationship studies of the enzymes belonging to the non-mevalonate pathway of Plasmodium falciparum
Project/Area Number |
23590495
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Parasitology (including Sanitary zoology)
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Research Institution | Showa University |
Principal Investigator |
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Project Period (FY) |
2011 – 2013
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Project Status |
Completed (Fiscal Year 2013)
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Budget Amount *help |
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | マラリア / 非メバロン酸経路 / ドラッグデザイン |
Research Abstract |
The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarials with novel modes of action. Fosmidomycin has proved to be efficient in the treatment of uncomplicated P. falciparum malaria in recent clinical trials conducted in Gabon and Thailand. It has a novel mode of action through the inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this study, we have successfully determined the crystal structures of P. falciparum DXR (PfDXR) in complex with alpha-aryl substituted fosmidomycin analogues, some of which have higher inhibitory activities (15 to 100 nM) against PfDXR. We expect present structures to be useful guides for the design of more effective antimalarial compounds.
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Binding modes of reverse fosmidomycin analogs towards the antimalarial target IspC2014
Author(s)
Konzuch, S., Umeda, T., Held, J., Hähn, S., Brücher, K., Lienau, C., Behrendt, C.T., Gräwert, T., Bacher, A., Illarionov, B., Fischer, M., Mordmuller, B., Tanaka, N., and Kurz, T.
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Journal Title
J. Med. Chem.
Volume: (submitted)
Related Report
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[Journal Article] Crystallization and preliminary X-ray crystallographic studies of dipeptidyl aminopeptidase BII from Pseudoxanthomonas Mexicana WO24.2014
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Okada, H., Nonaka, T., Morikawa, Y., Nakamura, K.T., Ogasawara. W., and Tanaka, N.*
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Journal Title
Acta Crystallogr. Section F
Volume: 70
Pages: 221-224
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[Journal Article] Identification of the catalytic triad of dipeptidyl aminopeptidase BII, a member of family S46 of exopeptidases that are closely related to clan PA endopeptidases.2014
Author(s)
Suzuki, Y., Sakamoto, Y., Tanaka, N., Okada, H., Morikawa, Y., and Ogasawara, W.*
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Journal Title
Related Report
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[Journal Article] Molecular basis of fosmidomycin’s action on the human malaria parasite Plasmodium falciparum.2011
Author(s)
Umeda, T., Tanaka, N., Kusakabe, Y., Nakanishi, M., Kitade, Y., & Nakamura, K.T.
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Journal Title
Scientific Reports
Volume: 1(9)
Issue: 1
Pages: 1-8
DOI
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Peer Reviewed
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[Presentation] Structural basis of fosmidomycin's action on Plasmodium falciparum2011
Author(s)
Tanaka, N., Umeda, T., Kusakabe, Y., Nakanishi, M., Kitade, Y., & Nakamura, K.T.
Organizer
XXII congress and general assembly of the International Union of Crystallography
Place of Presentation
マドリッド、スペイン
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