Structure-activity relationship studies of the enzymes belonging to the non-mevalonate pathway of Plasmodium falciparum

• Project/Area Number: 23590495
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Parasitology (including Sanitary zoology)
• Research Institution: Showa University
• Principal Investigator: TANAKA Nobutada 昭和大学, 薬学部, 准教授 (00286866)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥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)
• 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.

Research Products

• [Journal Article] Binding modes of reverse fosmidomycin analogs towards the antimalarial target IspC (2014)
  • 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.
  • Journal Title: J. Med. Chem. Volume: (submitted)
• [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.*
  • Journal Title: Acta Crystallogr. Section F Volume: 70 Pages: 221-224
• [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.*
  • Journal Title: Sci. Rep. Volume: 4
• [Journal Article] 抗マラリア薬の開発を目指した構造生物学的研究 (2013)
  • Author(s): 田中信忠、梅田知伸、日下部吉男、中西雅之、北出幸夫、中村和郎
  • Journal Title: 薬学雑誌 Volume: 133 Pages: 527-537
  • NAID: 130003361946
• [Journal Article] 抗マラリア薬の開発を指向した熱帯熱マラリア原虫由来ホスミドマイシン標的酵素の結晶構造解析 (2012)
  • Author(s): 梅田知伸、日下部吉男、田中信忠
  • Journal Title: 日本結晶学会誌 Volume: 54 Pages: 107-112
  • NAID: 10030631972
• [Journal Article] Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH (2012)
  • Author(s): Sundaram K, Endo S, Matsunaga T, Tanaka N, Hara A, El-Kabbani O.
  • Journal Title: Acta Crystallogr Sect F Struct Biol Cryst Commun. Volume: 68 Pages: 400-403
  • Peer Reviewed
• [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.
  • Journal Title: Scientific Reports Volume: 1(9) Issue: 1 Pages: 1-8
  • DOI: 10.1038/srep00009
  • Peer Reviewed
• [Presentation] Crystal structures of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) from Plasmodium falciparum complexed with inhibitors (2012)
  • Author(s): 梅田知伸、田中信忠、日下部吉男、中西雅之、北出幸夫、中村和郎
  • Organizer: 第11回アジア結晶学会
  • Place of Presentation: アデレード
• [Presentation] 熱帯熱マラリア原虫由来非メバロン酸経路関連酵素に関する構造生物学的研究 (2012)
  • Author(s): 葉梨繁樹、梅田知伸、中西雅之、北出幸夫、田中信忠
  • Organizer: 第56回日本薬学会関東支部大会
  • Place of Presentation: 東京
• [Presentation] 抗マラリア薬の開発を目指した構造生物学的研究 (2012)
  • Author(s): 田中信忠、梅田知伸、日下部吉男、中西雅之、北出幸夫、中村和郎
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] 抗マラリア薬の開発を目指した構造生物学的研究 (2012)
  • Author(s): 田中信忠、梅田知伸、日下部吉男、中西雅之、北出幸夫、中村和郎
  • Organizer: 日本薬学会(招待講演)
  • Place of Presentation: 北海道大学
• [Presentation] Structural basis of fosmidomycin's action on Plasmodium falciparum (2011)
  • 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
• [Presentation] ホスミドマイシン標的酵素の立体構造 (2011)
  • Author(s): 梅田知伸、田中信忠、日下部吉男、中西雅之、北出幸夫、中村和郎
  • Organizer: 第28回PFシンポジウム
  • Place of Presentation: つくば
• [Presentation] 抗マラリア新薬の開発を目指して (2011)
  • Author(s): 田中 信忠
  • Organizer: 未来のバイオ技術勉強会(招待講演)
  • Place of Presentation: 高エネルギー加速器研究機構
• [Presentation] P. mexicana WO24由来ジペプチジルアミノペプチダーゼの結晶構造解析
  • Author(s): 六本木沙織、館岡千佳、飯塚一平、鈴木義之、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 平成24年度日本結晶学会年会
  • Place of Presentation: 東北大学（仙台）
• [Presentation] Pseudoxanthomonas ｍexicana WO24由来アミノペプチダーゼの結晶構造解析
  • Author(s): 館岡千佳、六本木沙織、森澤さおり、飯塚一平、鈴木義之、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 第1回物構研サイエンスフェスタ
  • Place of Presentation: つくば国際会議場（つくば）
• [Presentation] Pseudoxanthomonas mexicana WO24由来ペプチド分解酵素の構造解析
  • Author(s): 館岡千佳、六本木沙織、森澤さおり、飯塚一平、鈴木義之、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Remarks] 高エネルギー加速器研究機構・研究ハイライトにおける紹介記事 「抗マラリア薬の開発を目指して」(2011年6月16日)
  • URL: http://www.kek.jp/ja/NewsRoom/Highlights/20110616131122/