Molecular basis for drug discovery of dipeptidyl amino peptidases from Non-Fermented Gram-Negative Rods

• Project/Area Number: 16K08322
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Iwate Medical University
• Principal Investigator: Sakamoto Yasumitsu 岩手医科大学, 薬学部, 准教授 (00349036)
• Research Collaborator: Roppongi Saori
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 抗菌薬 / NFGNR / 多剤耐性菌 / 歯周病菌 / 糖非発酵 / グラム陰性 / AMR / DPP / S46 / 多発性骨髄腫 / ジペプチジルアミノペプチダーゼ / 結晶構造解析 / SBDD / FE創薬 / 糖非発酵グラム陰性桿菌 / 酵素 / 感染症 / 蛋白質 / 構造生物

Outline of Final Research Achievements

Depletion of effective antimicrobials due to antimicrobial abuse is a serious threat of worldwide health. This research may lead to the development of new antimicrobials.
We developed compounds having an antibacterial effect against periodontitis bacteria(Porphyromonas gingivalis) and multidrug resistant bacteria (Stenotrophomonas maltophilia) using Structure Based Drug Design with Automated Research System for Drug Discovery.

Academic Significance and Societal Importance of the Research Achievements

2015年に採択されたWHOのアクションプランなどでは、MRSAなど緊急に新規抗菌薬の必要な菌種が取り上げられている。本研究対象のNFGNRであるStenotrophomonas maltophiliaやPorphyromonas gingivalisにも 既存の抗菌薬への耐性を有する菌株が出現しつつあり、MRSAなどに有効な抗菌薬との重複が見られる。これらNFGNRに対する特異的な抗菌薬開発は、単にそれらの菌を原因とする感染症の治療だけでなく、MRSAの治療に用いることのできる数少ない抗菌薬であるミノサイクリン、ST合剤およびマクロライド;系などの有効使用期間の延長にも繋がる。

Research Products

• [Journal Article] The Crystal Structure of Peptidase Toward Drug Discovery (2019)
  • Author(s): 阪本泰光、六本木沙織、鈴木義之、石原司、日高興士、中村彰宏、本間宣行、小笠原渉、田中信忠
  • Journal Title: International journal of microgravity science and application Volume: 36 Issue: 1 Pages: 360106
  • DOI: 10.15011//jasma.36.360106
  • NAID: 130007842629
  • ISSN: 2188-9783
  • Year and Date: 2019-01-31
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crystal structures of a bacterial dipeptidyl peptidase IV reveal a novel substrate recognition mechanism distinct from that of mammalian orthologues (2018)
  • Author(s): Roppongi Saori、Suzuki Yoshiyuki、Tateoka Chika、Fujimoto Mayu、Morisawa Saori、Iizuka Ippei、Nakamura Akihiro、Honma Nobuyuki、Shida Yosuke、Ogasawara Wataru、Tanaka Nobutada、Sakamoto Yasumitsu、Nonaka Takamasa
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2714-2714
  • DOI: 10.1038/s41598-018-21056-y
  • Peer Reviewed / Open Access
• [Journal Article] 微生物ジペプチジルアミノペプチダーゼIVの構造生物学的研究 (2018)
  • Author(s): 六本木沙織
  • Journal Title: 岩手医科大学大学院薬学研究科博士論文 Volume: 岩医大院薬博第4号 Pages: 1-112
  • Peer Reviewed
• [Journal Article] Periplasmic form of dipeptidyl aminopeptidase IV from Pseudoxanthomonas mexicana WO24: purification, kinetic characterization, crystallization and X‐ray crystallographic analysis (2017)
  • Author(s): Saori Roppongi Chika Tateoka Mayu Fujimoto Ippei Iizuka Saori Morisawa Akihiro Nakamura Nobuyuki Honma Yoshiyuki Suzuki Yosuke Shida Wataru Ogasawara Nobutada Tanaka Yasumitsu Sakamoto Takamasa Nonaka
  • Journal Title: Acta Crystallographica Section F Volume: 73 Issue: 11 Pages: 501-606
  • DOI: 10.1107/s2053230x17014911
  • Peer Reviewed / Open Access
• [Journal Article] Structural and Functional Studies of Dipeptidyl Aminopeptidase from Non-Fermenting Gram-Negative Rods (2016)
  • Author(s): 阪本泰光、野中孝昌、鈴木義之、小笠原渉、田中信忠
  • Journal Title: Nihon Kessho Gakkaishi Volume: 58 Issue: 5 Pages: 221-227
  • DOI: 10.5940/jcrsj.58.221
  • NAID: 130005267922
  • ISSN: 0369-4585, 1884-5576
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Crystal Structure of Dipeptidyl Peptidase 11 from Porphyromonas gingivalis: the Molecular Basis of Substrate Specificity among the Family S46 Peptidases (2016)
  • Author(s): Sakamoto Y, Tanaka N
  • Journal Title: Photon Factory Highlights Volume: 2015 Pages: 56-57
  • Open Access / Acknowledgement Compliant
• [Presentation] クスリ創りの新時代へ ～宇宙実験・アカデミア創薬・ロボット創薬のコラボレーションによる新薬創製への挑戦～ (2019)
  • Author(s): 阪本泰光, 田中信忠, 石原司
  • Organizer: 「きぼう」利用シンポジウム
• [Presentation] 宇宙を新薬設計に役立てる -基礎研究から民間利用への拡がり」 (2019)
  • Author(s): 西島和三、舛屋 圭一、細田雅人、阪本泰光、善光龍哉
  • Organizer: 「きぼう」利用シンポジウム
  • Invited
• [Presentation] ジペプチジルアミノペプチダーゼ 4 ファミリーの 立体構造比較研究 (2019)
  • Author(s): 六本木沙織 、鈴木義之 、館岡千佳 、藤本真友 、森澤さおり 、飯塚一平 、中村彰宏 、本間宣行 、伊藤康広 、志田洋介 、小笠原渉 、田中信忠 、阪本泰光 、野中孝昌
  • Organizer: 量子ビームサイエンスフェスタ
• [Presentation] Elucidation of substrate recognition mechanism of dipeptidyl aminopeptidase IV from Gram-negative bacteria (2019)
  • Author(s): Akihiro Nakamura, Nobuyuki Honma, Saori Roppongi, Yoshiyuki Suzuki, Yosuke Shida, Yasumitsu Sakamoto, Koji Inaka, Hiroaki Tanaka, Kiyoito Kihira, Mitsugu Yamada, Izumi Yoshioka, Hiroaki Gouda, Takamasa Nonaka, Nobutada Tanaka, Wataru Ogasawara
  • Organizer: 7th International GIGAKU conference in Nagaoka
  • Int'l Joint Research
• [Presentation] 「Stenotrophomonas maltophilia 由来 Dipeptidyl peptidase 7 の基質 P2 認識機構の解析」 (2019)
  • Author(s): 中村 彰宏、橋口 太一、本間 宣行、鈴木 義之、阪本 泰光、田中 信忠、小笠原 渉
  • Organizer: 日本農芸化学会2019年度大会
• [Presentation] 岩手と宇宙で拓く アカデミア創薬の取り組み」 (2018)
  • Author(s): 阪本泰光
  • Organizer: 盛岡経済研究会
  • Invited
• [Presentation] 微生物Dipeptidyl aminopeptidase IVの結晶構造解析 (2018)
  • Author(s): 六本木沙織、鈴木義之、館岡千佳、藤本真友、森澤さおり、飯塚一平、中村彰宏、本間宣行、伊藤康広、志田洋介、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 2017年度量子ビームサイエンスフェスタ
• [Presentation] Pseudoxanthomonas mexicana WO24由来Dipeptidyl aminopeptidase IVの構造・機能解析 (2018)
  • Author(s): 中村彰宏、本間宣行、六本木沙織、鈴木義之、志田洋介、阪本泰光、飯塚 一平、伊中 浩治、田仲広明、木平清人、山田貢、吉崎泉、合田浩明、野中孝昌、田中信忠、小笠原 渉
  • Organizer: 第12回 日本ゲノム微生物学会年会
• [Presentation] Pseudoxanthomonas mexicana WO24由来Dipeptidyl aminopeptidase IVの基質認識機構の解明 (2018)
  • Author(s): 中村彰宏、本間宣行、六本木沙織、鈴木義之、志田洋介、阪本泰光、飯塚一平、伊中浩治、田仲広明、木平清人、山田貢、吉崎泉、合田浩明、野中孝昌、田中信忠、小笠原渉
  • Organizer: 日本農芸化学会2018年度大会
• [Presentation] 部位特異的変異導入解析によるFamily S46ペプチダーゼの基質認識残基の同定 (2018)
  • Author(s): 本間宣行、中村彰宏、六本木沙織、鈴木義之、志田洋介、阪本泰光、飯塚一平、伊中浩治、田仲広明、木平清人、山田貢、吉崎泉、合田浩明、野中孝昌、田中信忠、小笠原渉
  • Organizer: 日本農芸化学会2018年度大会
• [Presentation] 微生物ジペプチジルアミノペプチダーゼIVの結晶構造解析 (2018)
  • Author(s): 六本木沙織、鈴木義之、館岡千佳、藤本真友、森澤さおり、飯塚一平、中村彰宏、本間宣行、伊藤康広、志田洋介、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 日本薬学会第138年会
• [Presentation] X線結晶構造に基づく多剤耐性菌由来DPP-7阻害剤の設計と評価 (2018)
  • Author(s): 関拓海、奥野優香、櫻井有紀、日高興士、宮崎杏奈、北條恵子、六本木沙織、阪本泰光、伊藤康広、鈴木義之、小笠原渉、田中信忠、木平清人、山田貢、吉崎泉、田仲広明、伊中浩治、津田裕子
  • Organizer: 日本薬学会第138年会
• [Presentation] 微生物ジペプチジルアミノペプチダーゼIVの結晶構造解析 (2018)
  • Author(s): 六本木沙織※、鈴木義之、館岡千佳、藤本真友、森澤さおり、飯塚一平、中村彰宏、本間宣行、伊藤康広、志田洋介、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 日本薬学会第138年会
• [Presentation] 糖非発酵グラム陰性細菌由来ペプチド分解酵素の結晶構造解析 (2017)
  • Author(s): ◯六本木沙織、館岡千佳、鈴木義之、伊藤康弘、藤本真友、森澤さおり、飯塚一平、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-25
• [Presentation] 糖非発酵グラム陰性細菌由来ジペプチジルアミノペプチダーゼ4の結晶構造解析 (2017)
  • Author(s): ◯六本木沙織、館岡千佳、鈴木義之、伊藤康弘、藤本真友、森澤さおり、飯塚一平、小笠原渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 2016年度量子ビームサイエンスフェスタ
  • Place of Presentation: つくば
  • Year and Date: 2017-03-14
• [Presentation] Identification for Substrate Recognition Residues in Family S46 Peptidase from Pathogenic Non-Fermenting Gram-Negative Bacteria (2017)
  • Author(s): Akihiro Nakamura、Yasuhiro Ito、Yoshiyuki Suzuki、Saori Roppongi、Koshi Hidaka、Yasumitsu Sakamoto、Nobutada Tanaka and Wataru Ogasawara
  • Organizer: International Union of Microbiogical Societies (IUMS) 2017
  • Int'l Joint Research
• [Presentation] S46 Family bacterial dipeptidyl aminopeptidases as novel antibiotics targets. (2017)
  • Author(s): Yasumitsu Sakamoto、Yoshiyuki Suzuki、Ippei Iizuka、Chika Tateoka、Saori Roppongi、Mayu Fujimoto、Yasuhiro Ito、Koji Inaka、Hiroaki Tanaka、Mitsugu Yamada、Kazunori Ohta、Hiroaki Gouda、Takamasa
  • Organizer: International Union of Microbiogical Societies (IUMS) 2017
  • Int'l Joint Research
• [Presentation] Crystal structures of dipeptidyl aminopeptidase IV from non-fermenting gram negative Rods. (2017)
  • Author(s): Saori Roppongi、Chika Tateoka、Mayu Fujimoto、Ippei Iizuka、Saori Morisawa、Akihiro Nakamura、Nobuyuki Honma、Yasuhiro Ito、Yoshiyuki Suzuki、Wataru Ogasawara、Nobutada Tanaka、Yasumitsu Sakamoto、Takamasa Nonaka
  • Organizer: International Union of Microbiogical Societies (IUMS) 2017
  • Int'l Joint Research
• [Presentation] Analysis of Substrate Recognition Residues in Family S46 Peptidase from Gram-Negative Bacteria (2017)
  • Author(s): Akihiro Nakamura、Yasuhiro Ito、Yoshiyuki Suzuki、Saori Roppongi、Koshi Hidaka、Yasumitsu Sakamoto、Nobutada Tanaka and Wataru Ogasawara
  • Organizer: 6th International GIGAKU conference in Nagaoka
  • Int'l Joint Research
• [Presentation] Identification of dipeptidic inhibitors targeting DPP7 derived from resistant multidrug resistant bacterium Stenotrophomonas maltophilia (2017)
  • Author(s): Yuki Sakurai、Koushi Hidaka、Anna Miyazaki、Keiko Hojo、Saori Roppongi、Yasumitsu Sakamoto、Yasuhiro Ito、Yoshiyuki Suzuki、Wataru Ogasawara、Nobutada Tanaka、and Yuko Tsuda
  • Organizer: 第54回ペプチド討論会
• [Presentation] Family S46 ペプチダーゼの新規基質認識残基の同定 (2017)
  • Author(s): 中村彰宏、伊藤康広、鈴木義之、六本木沙織、飯塚一平、阪本泰光、田中 信忠、小笠原 渉Family S46 ペプチダーゼの新規基質認識残基の同定
  • Organizer: 第17回 日本蛋白質科学会
• [Presentation] 宇宙実験での最近の成果 (2017)
  • Author(s): 阪本泰光
  • Organizer: iBIX-JAXA合同タンパク質研究会
  • Invited
• [Presentation] PFでの結晶化スクリーニングとプレートスクリーニングの現状 (2017)
  • Author(s): 阪本泰光
  • Organizer: 第2回PFユーザーグループ主催講習会
  • Invited
• [Presentation] Crystal structure analysis of bacterial dipeptidyl aminopeptidase IV (2016)
  • Author(s): ◯Roppongi, S., Tateoka, C., Suzuki, Y., Fujimoto, M., Morisawa, S., Iizuka, I., Kushibiki, C., Yonezawa, N., Ogasawara, W., Tanaka, N., Sakamoto, Y. and Nonaka, T.
  • Organizer: 14th Conference of the Asian Crystallographic Association
  • Place of Presentation: Hanoi
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Crystal Structure of Bacterial Dipeptidyl Aminopeptidase IV Complexed with Peptide (2016)
  • Author(s): Kushibiki, C., ◯Yonezawa, N., Roppongi, S., Tateoka, C., Suzuki, Y., Fujimoto, M., Morisawa, S., Iizuka, I., Ogasawara, W., Tanaka, N., Sakamoto, Y. and Nonaka, T.
  • Organizer: 14th Conference of the Asian Crystallographic Association
  • Place of Presentation: Hanoi
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Structural Analysis of Dipeptidyl Peptidase 11 (DPP11) from Porphyromonas gingivalis (2016)
  • Author(s): ◯Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.:
  • Organizer: 14th Conference of the Asian Crystallographic Association
  • Place of Presentation: Hanoi
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Structure and Functions of Dipeptidyl peptidase 11 (DPP11) from Porphyromonas gingivalis. (2016)
  • Author(s): SAKAMOTO Yasumitsu
  • Organizer: The 2nd International Symposium Space Science of High Quality Protein Crystallization Technology
  • Place of Presentation: Tokyo
  • Year and Date: 2016-10-21
  • Int'l Joint Research / Invited
• [Presentation] 多剤耐性菌由来DPP-7を標的とする阻害剤の設計と評価 －宇宙ステーションで抗菌薬を開発する (2016)
  • Author(s): ◯櫻井有紀、日高興士、宮崎杏奈、北條恵子、六本木沙織、阪本泰光、伊藤康広、鈴木義之、小笠原渉、田中信忠、津田裕子
  • Organizer: 第66回日本薬学会近畿支部大会
  • Place of Presentation: 大阪
  • Year and Date: 2016-10-15
• [Presentation] Enzymatic characterization of S46 peptidase from pathogenic bacteria (2016)
  • Author(s): ◯Ito, Y., Nakamura, A., Roppongi, S., Sakurai, Y., Suzuki, Y., Hidaka, K., Tsuda, Y., Sakamoto, Y., Tanaka, N. and Ogasawara, W.
  • Organizer: The 5th International GIGAKU Conference in Nagaoka (IGCN2016)
  • Place of Presentation: Nagaoka
  • Year and Date: 2016-10-07
  • Int'l Joint Research
• [Presentation] Crystal structure of dipeptidyl amino peptidase 11 from Porphyromonas gingivalis (2016)
  • Author(s): Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
  • Organizer: 42nd Naito Conference on "In the Vanguard of Structural Biology
  • Place of Presentation: Sapporo
  • Year and Date: 2016-10-06
• [Presentation] 糖非発酵グラム陰性細菌由来ペプチド分解酵素の結晶化と構造解析 (2016)
  • Author(s): 阪本泰光
  • Organizer: 東北大学金属材料研究所金属材料研究所ワークショップ
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-26
  • Invited
• [Presentation] 糖非発酵グラム陰性細菌由来ペプチド分解酵素の構造生物学的研究 (2016)
  • Author(s): ◯六本木沙織、館岡千佳、鈴木義之、藤本真友、森澤さおり、飯塚一平、小笠原 渉、田中信忠、阪本泰光、野中孝昌
  • Organizer: 第55回日本薬学会東北支部大会
  • Place of Presentation: 郡山
  • Year and Date: 2016-09-25
• [Presentation] Crystal Structure of Dipeptidyl Amino Peptidase 11 (DPP11) from Periodontal Pathogen. (2016)
  • Author(s): SAKAMOTO Yasumitsu
  • Organizer: ISS R&D Conference
  • Place of Presentation: San Diego
  • Year and Date: 2016-07-14
  • Int'l Joint Research / Invited
• [Presentation] Structure analysis of dipeptidyl peptidase 11 from Porphyromonas gingivalis. (2016)
  • Author(s): Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N
  • Organizer: 16th International Conference on the Crystallization of Biological Macromolecules
  • Place of Presentation: Prague
  • Year and Date: 2016-07-05
  • Int'l Joint Research
• [Presentation] Structure-Function Relationships of S46 peptidases from Non-Fermenting Gram-Negative Rods (2016)
  • Author(s): Roppongi, S., Suzuki, I., Iizuka, I., Inaka, K., Tanaka, H., Yamada, M., Ohata, K., Nonaka, T., Ogasawara, W., Tanaka, N. and Sakamoto, Y.
  • Organizer: American Society for Microbiology
  • Place of Presentation: Boston
  • Year and Date: 2016-06-17
  • Int'l Joint Research
• [Presentation] S46ペプチダーゼの構造機能相関の解明 (2016)
  • Author(s): ○伊藤康広、鈴木義之、阪本泰光、田中信忠、小笠原渉
  • Organizer: 第16回日本蛋白質科学会
  • Place of Presentation: 福岡
  • Year and Date: 2016-06-07
• [Presentation] 歯周病原菌Porphyromonas gingivalis由来dipeptidyl peptidase 11の精製と機能解析 (2016)
  • Author(s): 中村彰宏、伊藤康広、鈴木義之、志田洋介、阪本泰光、田中信忠、小笠原渉
  • Organizer: 第16回日本蛋白質科学会
  • Place of Presentation: 福岡
  • Year and Date: 2016-06-07
• [Book] International Space Station Benefits for Humanity 3rd Edition (2019)
  • Author(s): NASA 他
  • Total Pages: 221
  • Publisher: NASA
• [Book] International Space Station Benefits for Humanity 3rd Edition 日本語ダイジェスト版 (2019)
  • Author(s): JAXA 他
  • Total Pages: 55
  • Publisher: JAXA
• [Remarks] ISSがもたらす人類への恩恵
  • URL: http://iss.jaxa.jp/kiboresults/benefits/
• [Remarks] ISS Benefit for Humanity
  • URL: https://www.nasa.gov/sites/default/files/atoms/files/benefits-for-humanity_third.pdf
• [Remarks] 人類最大の感染症「歯周病」に迫る
  • URL: http://iss.jaxa.jp/kiboexp/theme/first/protein/interview/interview02.html
• [Remarks] 岩手医科大学などの研究グループ、糖尿病薬や抗がん剤開発に役立つ酵素の立体構造を解明 高エネ研
  • URL: https://www2.kek.jp/imss/news/2018/topics/0209DAP4/
• [Remarks] 副作用の少ない糖尿病薬や抗がん剤の開発に結びつく酵素の立体構造を解明しました 岩手医科大学
  • URL: https://www.iwate-med.ac.jp/news/n5-research/kikaku-180209/
• [Remarks] 選択性が高く副作用の少ないDPP-4阻害薬の開発へ 酵素の立体構造を解明 糖尿病ネット
  • URL: http://dm-rg.net/news/2018/02/018470.html?pr=dmrg001
• [Remarks] DPP4阻害薬のオフターゲット「DPP8/9」の類縁酵素の立体構造を解明－岩手医科大 医療ニュース
  • URL: http://www.qlifepro.com/news/20180215/stereostructure-of-dpp-8-9-related-enzyme.html
• [Remarks] ISS Award
  • URL: https://www.nasa.gov/mission_pages/station/research/news/compelling_science_awards_2016/
• [Remarks] JAXA トピックス
  • URL: http://iss.jaxa.jp/topics/2016/07/160715.html
• [Patent(Industrial Property Rights)] 細菌由来ジペプチジルペプチダーゼの酵素活性を阻害するジペプチド誘導体 (2017)
  • Inventor(s): 阪本泰光、日高興士、津田裕子、小笠原渉
  • Industrial Property Rights Holder: 阪本泰光、日高興士、津田裕子、小笠原渉
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-156345
  • Filing Date: 2017