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

2013 Fiscal Year Final Research Report

• 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
• 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] 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
• [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
• [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
  • Year and Date: 20121200
• [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
  • Year and Date: 20121000
• [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
  • Year and Date: 20120300
• [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
  • Year and Date: 20110800
• [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
  • Year and Date: 20110700
• [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/