Chemical biology of cyanide-insensitive Trypanosome alternative oxidase.

• Project/Area Number: 26253025
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Parasitology (including sanitary zoology)
• Research Institution: Nagasaki University (2016); The University of Tokyo (2014-2015)
• Principal Investigator: KITA Kiyoshi 長崎大学, 熱帯医学・グローバルヘルス研究科, 教授 (90134444)
• Co-Investigator(Kenkyū-buntansha): 稲岡 健ダニエル 東京大学, 医学(系)研究科(研究院), 助教 (10623803)
• Co-Investigator(Renkei-kenkyūsha): HARADA Shigeharu 京都工芸繊維大学, 工芸科学研究科, 教授 (80156504) ; SAIMOTO Hiroyuki 鳥取大学, 工学研究科, 教授 (20186977)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥39,910,000 (Direct Cost: ¥30,700,000、Indirect Cost: ¥9,210,000); Fiscal Year 2016: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000); Fiscal Year 2015: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2014: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
• Keywords: シアン耐性酸化酵素 / トリパノソーマ / アスコフラノン / 生合成 / シアン耐酸化酵素

Outline of Final Research Achievements

We have shown the parasite energy metabolism enzymes has extremely special properties and plays an important role in adaptation in the host. Trypanosome alternative oxidase is essential for the growth of African trypanosome inhabiting the host's bloodstream and is a promising enzyme as a drug target.
We focused on the specific inhibitor ascofuranone which we discovered. Characteristics of the enzyme, its interaction with inhibitors and biosynthesis of ascofuranone have been studied from a standpoint of chemical biology which includes chemical approaches as well as general biology and keeps mind application.

Research Products

• [Journal Article] Design and Synthesis of Potent Substrate-based Inhibitors of the Trypanosoma cruzi Dihydroorotate Dehydrogenase (2017)
  • Author(s): D. K. Inaoka, M. Iida, S. Hashimoto, T. Tabuchi,T. Kuranaga, E. O. Balogun, T. Honma, A. Tanaka, S. Harada, T. Nara, K. Kita, M. Inoue
  • Journal Title: Bioorg. Med. Chem. Volume: 25 Issue: 4 Pages: 1465-1470
  • DOI: 10.1016/j.bmc.2017.01.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor (2017)
  • Author(s): Masaki Ohtawa, Shiho Arima, Risa Shimizu, Naomi Hanatani, Eri Shimizu, Kazuro Shiomi, Kiyoshi Kita, Satoshi Omura,Tohru Nagamitsu
  • Journal Title: The Journal of Antibiotics(Tokyo) Volume: 印刷中 Issue: 5 Pages: 647-654
  • DOI: 10.1038/ja.2017.16
  • Peer Reviewed
• [Journal Article] Investigation into the ubiquinol-binding site of the trypanosomal alternative oxidase (2016)
  • Author(s): Benjamin May, Luke Young, Mary Albury, Daniel Ken Inaoka, Kiyoshi Kita, Anthony L. Moore
  • Journal Title: Biochimica et Biophysica Acta (BBA)-Bioenergetics Volume: 1857 Pages: e41-e41
  • DOI: 10.1016/j.bbabio.2016.04.309
  • Int'l Joint Research
• [Journal Article] Drug selection using bleomycin for transfection of the oyster-infecting parasite Perkinsus marinus (2016)
  • Author(s): Sakamoto H, Kita K, Matsuzaki M
  • Journal Title: Parasitology International Volume: 未定 Issue: 5 Pages: 563-566
  • DOI: 10.1016/j.parint.2016.04.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Open Form Inducer Approach for Structure-Based Drug Design (2016)
  • Author(s): D. K. Inaoka, M. Iida, T. Tabuchi, T. Honma, N. Lee, S. Hashimoto, S. Matsuoka, T. Kuranaga, K. Sato, T. Shiba, K. Sakamoto, E. O. Balogun, S. Suzuki, T. Nara, J. R. Rocha, C. A. Montanari, A. Tanaka, M. Inoue, K. Kita, S. Harada
  • Journal Title: PLoS ONE Volume: 11 Issue: 11 Pages: e0167078-e0167078
  • DOI: 10.1371/journal.pone.0167078
  • NAID: 120006987593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation into the Physiological Significance of the Phytohormone Abscisic Acid in Perkinsus marinus, an Oyster Parasite Harboring a Non-Photosynthetic Plastid (2016)
  • Author(s): Sakamoto, H, Suzuki, S., Nagamune, K., Kita, K., Matsuzaki, M.
  • Journal Title: J. Eukaryot. Microbiol. Volume: 印刷中 Issue: 4 Pages: 440-446
  • DOI: 10.1111/jeu.12379
  • Peer Reviewed / Open Access
• [Journal Article] Parasites resistant to the anti-malarial atovaquone fail to transmit by mosquitoes. (2016)
  • Author(s): Goodman, C. D., Siregar, J., Mollard, V., Vega-Rodriguez, J., Syafruddin, D., Matsuoka, H., Matsuzaki, M., Toyama, T., Sturm, A., Cozijnsen, A., Jacobs-Loreno, M., Kita, K., Marzuki, S. and McFadden, G. I.
  • Journal Title: Science Volume: 352 Pages: 349-353
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lactate retards the development of erythrocytic stages of the human malaria parasite Plasmodium falciparum. (2015)
  • Author(s): Hikosaka K, Hirai M, Komatsuya K, Ono Y, Kita K.
  • Journal Title: Parasitol Int Volume: 64 Issue: 3 Pages: 301-303
  • DOI: 10.1016/j.parint.2014.08.003
  • Peer Reviewed / Open Access
• [Journal Article] 2.Pharmacophore Modeling for Anti-Chagas Drug Design Using the Fragment Molecular Orbital Method (2015)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo curative and protective potential of orally administrated 5-aminolevulinic acid plus ferrous iron against malaria (2015)
  • Author(s): Suzuki S, Hikosaka K, Balogun EO, Komatsuya K, Niikura M, Kobayashi F, Takahashi K, Tanaka T, Nakajima M, Kita K.
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 59 Issue: 11 Pages: 6960-6967
  • DOI: 10.1128/aac.01910-15
  • Peer Reviewed / Open Access
• [Journal Article] Direct evidence for the atovaquone action on the Plasmodium cytochrome bc1 complex. (2015)
  • Author(s): Siregar JE, Kurisu G, Kobayashi T, Matsuzaki M, Sakamoto K, Mi-Ichi F, Watanabe Y, Hirai M, Matsuoka H, Syafruddin D, Marzuki S, Kita K.
  • Journal Title: Parasitol Int Volume: 64 Issue: 3 Pages: 295-300
  • DOI: 10.1016/j.parint.2014.09.011
  • Peer Reviewed / Open Access
• [Presentation] Diversity of respiratory chains in parasite mitochondria - As a drug target - (2017)
  • Author(s): Kiyoshi Kita
  • Organizer: the 115th International Titisee Conference
  • Place of Presentation: Treschers Schwarzwaldhotel (Mainz, Germany)
  • Year and Date: 2017-03-29
  • Int'l Joint Research / Invited
• [Presentation] NTDｓと治療薬の現状と課題 (2017)
  • Author(s): 北 潔
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2017-03-25
  • Invited
• [Presentation] ミトコンドリア呼吸鎖電子伝達系 -創薬ターゲットとして- (2016)
  • Author(s): 北 潔
  • Organizer: 日本生物工学会第23回九州支部飯塚大会
  • Place of Presentation: 九州工業大学（福岡県、飯塚市）
  • Year and Date: 2016-12-03
  • Invited
• [Presentation] Re-modeling of respiratory chain in the parasite mitochondria during their adaptation環境適応における寄生虫ミトコンドリア呼吸鎖のリモデリング (2016)
  • Author(s): 北 潔
  • Organizer: 第54回日本生物物理学会年会
  • Place of Presentation: つくば国際会議場（茨城県、つくば市）
  • Year and Date: 2016-11-27
  • Invited
• [Presentation] 熱帯感染症制圧へ向けての創薬 -薬剤標的としてのミトコンドリア- (2016)
  • Author(s): 北 潔
  • Organizer: 中高温微生物研究センター・シンポジウム 「熱帯感染症の制圧に向けて」
  • Place of Presentation: 山口大学（山口県、山口市）
  • Year and Date: 2016-11-25
  • Invited
• [Presentation] Mitochondria as drug target -from parasites to cancer cells (2016)
  • Author(s): Kiyoshi Kita
  • Organizer: The 13th Conference of Asian Society for Mitochondrial Research and Medicine, The 16th Conference of Japanese Society of Mitochondrial Research and Medicine
  • Place of Presentation: TKPガーデンシティ品川（東京都、港区）
  • Year and Date: 2016-10-30
  • Int'l Joint Research / Invited
• [Presentation] 新規抗エキノコックス薬の開発 -ミトコンドリアを標的として- (2016)
  • Author(s): 北 潔
  • Organizer: 青海大学-宮崎大学合同シンポジウム －エキノコックス対策-
  • Place of Presentation: 中国青海大学畜牧獣医科学院 (青海省西寧市, 中国）
  • Year and Date: 2016-09-12
  • Int'l Joint Research / Invited
• [Presentation] 新規抗マラリア薬としての5－アミノレブリン酸 (2016)
  • Author(s): 北 潔
  • Organizer: 第6回ポルフィリン-ALA学会年会
  • Place of Presentation: 東京大学医科学研究所（東京都、港区）
  • Year and Date: 2016-04-22
  • Invited
• [Presentation] Magic Bullets for Parasitic Diseases - Drugs from Japan - (2016)
  • Author(s): KITA Kiyoshi
  • Organizer: 日本薬理学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] Ascofuranone: a gift from nature as anti-parasite drug (2016)
  • Author(s): KITA Kiyoshi
  • Organizer: US-Japan EID Meeting - 50th Anniversary
  • Place of Presentation: Bethesda, USA
  • Year and Date: 2016-01-11
  • Int'l Joint Research / Invited
• [Presentation] 低酸素適応におけるミトコンドリアの役割：寄生虫からがん細胞まで (2014)
  • Author(s): 北 潔
  • Organizer: 第14回日本ミトコンドリア学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2014-12-04
  • Invited
• [Presentation] 寄生虫の低酸素エネルギー代謝経路を標的にした構造生命科学による創薬 (2014)
  • Author(s): 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: 2014-10-16
• [Presentation] ミトコンドリア呼吸鎖の多様性：寄生虫からがん細胞まで (2014)
  • Author(s): 北 潔
  • Organizer: 第52回生物物理学会
  • Place of Presentation: 札幌
  • Year and Date: 2014-09-26
  • Invited
• [Book] Kala Azar in South Asia (2017)
  • Author(s): Nozomu Nihashi, Daniel Ken Inaoka, Chiaki Tsuge, Emmanuel Oluwadare Balogun, Yasutaka Osada, Yasuyuki Goto, Yoshitsugu Matsumoto, Takeshi Nara, Tatsushi Mogi, Shigeharu Harada, Kita Kiyoshi
  • Total Pages: 309
  • Publisher: Springer International Publishing
• [Book] Cytochrome Complexes:Evolution, Structures, Energy Transduction, and Signaling (2016)
  • Author(s): Luke Young, Benjamin May, Tomoo Shiba, Shigeharu Harada, Daniel Ken Inaoka, Kiyoshi Kita, Anthony L. Moore
  • Total Pages: 739
  • Publisher: Springer Netherlands
• [Remarks] 東京大学大学院国際保健学専攻・生物医化学教室
  • URL: http://www.biomedchem.m.u-tokyo.ac.jp/
• [Patent(Industrial Property Rights)] Dihydroorotic and acid dehydrogenase inhibitor (2016)
  • Inventor(s): Kiyoshi Kita, et al.
  • Industrial Property Rights Holder: Kiyoshi Kita, et al.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-06-14
  • Overseas
• [Patent(Industrial Property Rights)] Endoparasite control agent and method for using the same (2016)
  • Inventor(s): Kiyoshi Kita, et al.
  • Industrial Property Rights Holder: Kiyoshi Kita, et al.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-09-15
  • Overseas
• [Patent(Industrial Property Rights)] Endoparasite control agent (2016)
  • Inventor(s): Kiyoshi Kita, et al.
  • Industrial Property Rights Holder: Kiyoshi Kita, et al.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-10-20
  • Overseas