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Drug development of African sleeping sickness targeting energy metabolic pathway

Research Project

Project/Area Number 26440027
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Structural biochemistry
Research InstitutionKyoto Institute of Technology

Principal Investigator

Shiba Tomoo  京都工芸繊維大学, 応用生物学系, 准教授 (80401206)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsトリパノソーマ / 顧みられない熱帯病 / エネルギー代謝 / 二核鉄タンパク質 / 膜表剤型タンパク質 / アスコフラノン / X線結晶構造解析 / 顧みられい熱帯病 / diironタンパク質 / 膜表在型タンパク質 / X線結晶構造解析
Outline of Final Research Achievements

The trypanosome cyanide-insensitive alternative oxidase (TAO) and trypanosome glycerol kinase (TGK) are drug targets for human African sleeping sickness. In this study, I determined the crystal structures of TAO and TGK in complex with its lead compounds to make more potent drug. The crystal structure of TAO in complex with its new inhibitor, ferulenol was determined at 2.7 Å resolution. I found GK-17b which is a novel inhibitor of TGK. In addition, this compound inhibits TAO enzymatic activity with comparable strength.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (17 results)

All 2017 2016 2015 2014

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Int'l Joint Research: 1 results) Book (1 results)

  • [Journal Article] Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion.2017

    • Author(s)
      Francisco Jose Fueyo Gonzalez, Godwin U. Ebiloma, Carolina Izquierdo Garcia, Victor Bruggeman, Jose Maria Sanchez Villamanan, Anne Donachie, Emmanuel Oluwadare Balogun, Daniel Ken Inaoka, Tomoo Shiba, Shigeharu Harada, Kiyoshi Kita, Harry P. de Koning, Christophe Dardonville
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 60(4) Issue: 4 Pages: 1509-1522

    • DOI

      10.1021/acs.jmedchem.6b01740

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The hyperthermophilic cystathionine γ-synthase from the aerobic crenarchaeon Sulfolobus tokodaii: expression, purification, crystallization and structural insights2017

    • Author(s)
      Sato D, Shiba T, Mizuno S, Kawamura A, Hanada S, Yamada T, Shinozaki M, Yanagitani M, Tamura T, Inagaki K, Harada S
    • Journal Title

      Acta Cryst., F

      Volume: 73 Issue: 3 Pages: 152-158

    • DOI

      10.1107/s2053230x17002011

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural and mechanistic insights into homocysteine degradation by a mutant of methionine γ-lyase based on substrate-assisted catalysis2017

    • Author(s)
      Sato D, Shiba T, Yunoto S, Furutani K, Fukumoto M, Kudou D, Tamura T, Inagaki K, Harada S.
    • Journal Title

      Protein Science

      Volume: 26 Issue: 6 Pages: 152-158

    • DOI

      10.1002/pro.3158

    • NAID

      130007628790

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 1.Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria2015

    • Author(s)
      Inaoka DK, Shiba T, Sato D, Balogun EO, Sasaki T, Nagahama M, Oda M, Matsuoka S, Ohmori J, Honma T, Inoue M, Kita K, Harada S
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 16 Issue: 7 Pages: 15287-15308

    • DOI

      10.3390/ijms160715287

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] 2.Pharmacophore Modeling for Anti-Chagas Drug Design Using the Fragment Molecular Orbital Method2015

    • Author(s)
      Yoshino R, Yasuo N, Inaoka DK, Hagiwara Y, Ohno K, Orita M, Inoue M, Shiba T, Harada S, Honma T, Balogun EO, da Rocha JR, Montanari CA, Kita K, Sekijima M
    • Journal Title

      PLoS One

      Volume: 10 Issue: 5 Pages: 1-15

    • DOI

      10.1371/journal.pone.0125829

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Probing the ubiquinol-binding site of recombinant Sauromatum guttatum alternative oxidase expressed in E. coli membranes through site-directed mutagenesis2014

    • Author(s)
      Luke Young, Benjamin May, Alice Pendlebury-Watt, Julia Shearman, Catherine Elliott, Mary S. Albury, Tomoo Shiba, Daniel Ken Inaoka, Shigeharu Harada, Kiyoshi Kita, Anthony L. Moore
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Bioenergetics

      Volume: 1837 Issue: 7 Pages: 1219-1225

    • DOI

      10.1016/j.bbabio.2014.01.027

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular basis for the reverse reaction of African human trypanosomes glycerol kinase2014

    • Author(s)
      Emmanuel Oluwadare Balogun, Daniel Ken Inaoka, Tomoo Shiba, Yasutoshi Kido, Chiaki Tsuge, Takeshi Nara, Takashi Aoki, Teruki Honma, Akiko Tanaka, Masayuki Inoue, Shigeru Matsuoka, Paul A.M. Michels, Kiyoshi Kita, Shigeharu Harada
    • Journal Title

      Molecular Microbiology

      Volume: 94 Issue: 6 Pages: 1315-1329

    • DOI

      10.1111/mmi.12831

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] 微生物からの贈り物アスコフラノン - アフリカ睡眠病からがん細胞まで -2014

    • Author(s)
      北潔, 志波智生, 斎本博之, 稲岡ダニエル健, 原田繁春
    • Journal Title

      MEDCHEM NEWS

      Volume: 24-4 Pages: 44-50

    • NAID

      130007674627

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] Serendipitous discovery of trypanocidal compounds with dual-inhibition for African trypanosomes glycerol kinase and alternative oxidase2016

    • Author(s)
      Emmnuel O. Balogun, Daniel K. Inaoka, Tomoo Shiba, Chiaki Tsuge, Benjamin May, Tomohiro Sato, Yasutoshi Kido, Takeshi Nara, Takashi Aoki, Teruki Honma, Akiko Tanaka, Masayuki Inoue, Shigeru Matsuoka, Paul A.M. Michels, Anthony L Moore, Shigeharu Harada, Kiyoshi Kita
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] アフリカトリパノソーマのシアン耐性酸化酵素(TAO)とクマリン骨格をもつ新規阻害剤との複合体結晶構造2016

    • Author(s)
      西藤万智, 志波智生, 上田慧, 稲岡ダニエル健, 城戸康年, バログン エマニエル, アントニー ムーア, 斎本博之, 北潔, 原田繁春
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] トリパノソーマシアン耐性酸化酵素(TAO)とグリセロールキナーゼ(GK)の結晶構造2015

    • Author(s)
      志波智生、エマニュエルバログン、稲岡ダニエル健、原田繁春、北潔
    • Organizer
      第41回生体エネルギー研究会討論会
    • Place of Presentation
      東京
    • Year and Date
      2015-12-21
    • Related Report
      2015 Research-status Report
  • [Presentation] The crystal structures of trypanosomal cyanide-insensitive alternative oxidase (TAO) and glycerol kinase (GK)2015

    • Author(s)
      Tomoo Shiba, Emmanuel Oluwadare Balogun, Daniel Ken Inaoka, Shigeharu Harada, Kiyoshi Kita
    • Organizer
      3rd International Picobiology Institute Symposium
    • Place of Presentation
      兵庫県立大学
    • Year and Date
      2015-12-08
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] アフリカトリパノソーマのシアン耐性酸化酵素(TAO)と異なる骨格を持つ阻害剤、アスコフラノン及びフェルレノールとの複合体構造2015

    • Author(s)
      上田 慧、中井万智、志波 智生、高橋 元、 稲岡 ダニエル健、城戸 康年、坂元 君年、 柘植 千明、Emmanuel Oluwadare Balogun、奈良武司、青木孝、本間 光貴、田仲 昭子、井上将行、松岡茂、Moore L. Anthony、斎本 博之、 北 潔、原田 繁春
    • Organizer
      第88回日本生化学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Research-status Report
  • [Presentation] Glycerol kinase from human African trypanosomes possess an intrinsic acid phosphatase activity2014

    • Author(s)
      Balogun Emmanuel O., Inaoka Daniel K., Shiba Tomoo, Sakamoto Kimitoshi, Kido Yasutoshi, Nara Takeshi, Aoki Takashi, Honma Teruki, Tanaka Akiko, Inoue Masayuki, Matsuoka Shigeru, Michels Paul AM., Harada Shigeharu, Kita Kiyoshi
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-15 – 2014-10-18
    • Related Report
      2014 Research-status Report
  • [Presentation] アフリカトリパノソーマのシアン耐性酸化酵素 (TAO)と新規阻害剤: フェルレノールとの複合体の結晶構造2014

    • Author(s)
      上田慧、志波智生、高橋元、稲岡ダニエル健、城戸康年、坂元君年、柘植千明、Emmanuel Oluwadare Balogun、奈良武司、青木孝、本間光貴、田仲昭子、井上将行、松岡茂、Anthony L. Moore、斎本博之、原田繁春、北潔
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-15 – 2014-10-18
    • Related Report
      2014 Research-status Report
  • [Presentation] アフリカトリパノソーマのシアン耐性酸化酵素(TAO)と新規阻害剤:フェルレノールとの複合体晶構造2014

    • Author(s)
      上田 慧、志波 智生、高橋 元、稲岡 ダニエル健、城戸 康年、坂元 君年、柘植 千明、本間 光貴、田仲 昭子、斎本 博之、北 潔、原田 繁春
    • Organizer
      第14回日本蛋白質科学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2014-06-25 – 2014-06-27
    • Related Report
      2014 Research-status Report
  • [Book] Cytochrome Complexes: Evolution, Structures, Energy Transduction, and Signaling, Chapter 19, Structure and Mechanism of Action of the Alternative Quinol Oxidases2016

    • Author(s)
      Young L, May B, Shiba T, Harada S, Inaoka DK, Kita K, Moore AL
    • Total Pages
      739
    • Publisher
      Springer
    • Related Report
      2016 Annual Research Report

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Published: 2014-04-04   Modified: 2018-03-22  

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