Drug discovery research: Searching for a new antibiotics based on stable phospho-histidine mimics

• Project/Area Number: 24510311
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: Nagasaki International University
• Principal Investigator: Yamaguchi Yasuchika 長崎国際大学, 薬学部, 教授 (10183980)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Keitaro 長崎国際大学, 薬学部, 講師 (60446127) ; HAGIMORI Masayori 長崎大学, 薬学部, 准教授 (40446125)
• Research Collaborator: KINO Toru
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ホスホヒスチジン / ペプチドライブラリー / 抗菌活性

Outline of Final Research Achievements

The purpose of this study was searching for potential new antibiotics targeting bacterial two-component signal transduction system. Our achievements, so far are following: 1) We established stereoselective and scalable amino acid synthesis based on Schoelkopf chemistry. 2) We prepared enough quantity of the phosphor-histidine mimic. 3) Synthetic method for peptides containing the mimic is established. 4) Deprotection protocol for generating free phophoric acid is invented. 5) Rapid and cheap synthesis method for dipeptide mimics is developed. Biological assay for antibiotic activities are still on going.

Research Products

• [Journal Article] n-vitro Anti-trypanosomal Activities and Mechanisms of Action of Novel Tetracyclic Iridoids from Morinda lucida Benth (2016)
  • Author(s): K Kwofie, N Tung, M Suzuki-Ohashi, M Amoa-Bosompem, R Adegle, M Sakyiamah, F Ayertey, K Owusu, I Tuffour, P Atchoglo, K Frempong, W Anyan, T Uto, O Morinaga, T Yamashita, F Aboagye, A Appiah, R Appiah-Opong, A Nyarko, Y Yamaguchi, D Edoh, K Koram, S Yamaoka, D Boakye, N Ohta, Y Shoyama, I Ayi
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 60 Issue: 6 Pages: 3283-3290
  • DOI: 10.1128/aac.01916-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Determination of the absolute configuration of the novel anti-trypanosomal iridoid molucidin isolated from Morinda lucida by X-ray analysis, (2015)
  • Author(s): Satoru Karasawa, Kenji Yoza, Nguyen Huu Tung, Takuhiro Uto, Shoji Yamaoka, Nobuo Ohta, Yukihiro Shoyama, 外27名、
  • Journal Title: Tetrahedron Lett. Volume: 56 Issue: 52 Pages: 7158-7160
  • DOI: 10.1016/j.tetlet.2015.11.031
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A high-affinity fluorescent Zn2+ sensor improved by the suppression of pyridine-pyridone tautomerism and its application in living cells (2015)
  • Author(s): Masayori Hagimori, Takashi Temma, Naoko Mizuyama, Takuhiro Uto, Yasuchika Yamaguchi, Yoshinori Tominaga, Takahiro Mukai, and Hideo Saji
  • Journal Title: Sensors and Actuators B: Chemical Volume: 213 Pages: 45-52
  • DOI: 10.1016/j.snb.2015.02.063
  • Peer Reviewed
• [Journal Article] New anti-trypanosomal active tetracyclic irridoid isolated from Morinda lucida Benth (2015)
  • Author(s): M Suzuki; NH Tung; KD Kwofie; R Adegle; M Amoa-Bosompem; M Sakyiamah; F Ayertey; KB-A Owusu; I Tuffour; P Atchoglo; KK Frempong; WK Anyan; T Uto; O Morinaga; T Yamashita; F Aboagye; AA Appiah; R Appiah-Opong; AK Nyarko; . Yamaoka; Y Yamaguchi; D Edoh; K Koram; N Ohta; DA Boakye; I Ayi; Y Shoyama
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 25 Issue: 15 Pages: 0-0
  • DOI: 10.1016/j.bmcl.2015.05.003
  • Peer Reviewed
• [Journal Article] 亜鉛イオン応答性ピリジン－ピリドン型蛍光プローブを用いた細胞内亜鉛分布解析への挑戦 （その1）/ Challenges to detect an intracellular localization of zinc ion by Zn2+ responsive fluorescent probe, a pyridine-pyridone derivative (2015)
  • Author(s): 藤田英明、楢崎彩香、大久保麻佳、藤井佑樹、藤原俊幸、萩森政頼、山口泰史 / Hideaki FUJITA, Ayaka NARAZAKI, Asaka OHKUBO, Yuki FUJII, Toshiyuki FUJIWARA, Masayori HAGIMORI, Yasuchika YAMAGUCHI
  • Journal Title: 長崎国際大学論叢 / Nagasaki International University review Volume: 15 Pages: 186-192
  • Peer Reviewed
• [Journal Article] Anti-Trypanosomal Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica (2014)
  • Author(s): Nguyen Huu Tung, Mitsuko Suzuki, Takuhiro Uto, Osamu Morinaga, Kofi D. Kwofie, Naa Ammah, Kwadwo A. Koram, Frederic Aboagye, Dominic Edoh, Taizo Yamashita, Yasuchika Yamaguchi, Takao Setsu, Shoji Yamaoka, Nobuo Ohta, Yukihiro Shoyama
  • Journal Title: The American Journal of Chinese Medicine Volume: 42 Pages: 1245-1260
  • Peer Reviewed
• [Journal Article] 体験から考える創薬化学2： Es war einmal./Once upon a time. (2014)
  • Author(s): 山口 泰史
  • Journal Title: MEDCHEM NEWS Volume: 24(4) Pages: 8-11
  • NAID: 130007674620
• [Journal Article] Anti-trypanosomal Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica Steud. (2014)
  • Author(s): Nguyen Huu Tung, Mitsuko Suzuki, Takuhiro Uto, Osamu Morinaga, Kofi D. Kwofie, Naa Ammah, Kwadwo A. Koram, Frederic Aboagye, Dominic Edoh, Taizo Yamashita, Yasuchika Yamaguchi, Takao Setsu, Shoji Yamaoka, Nobuo Ohta and Yukihiro Shoyama
  • Journal Title: The American Journal of Chinese Medicine Volume: 42 Pages: 0-0
  • Peer Reviewed
• [Journal Article] 体験から考える創薬化学：Es war einmal./Once upon a time. (2013)
  • Author(s): 山口泰史
  • Journal Title: MEDCHEM NEWS Volume: 23 Pages: 6-10
  • NAID: 130007869038
• [Journal Article] Fluorescence ON/OFF switching Zn2+ sensor based on pyridine-pyridone scaffold (2013)
  • Author(s): Masayori Hagimori, Takuhiro Uto, Naoko Mizuyama, Takashi Temma, Yasuchika Yamaguchi, Yoshinori Tominaga, Hideo Saji
  • Journal Title: Sensors and Actuators B: Chemical Volume: 181 Pages: 823-828
  • Peer Reviewed
• [Journal Article] 体験から考える創薬化学：Es war einmal. / Once upon a time. (2013)
  • Author(s): 山口泰史
  • Journal Title: MEDCHEM NEWS Volume: 23 Pages: 6-10
  • NAID: 130007869038
• [Presentation] 分子内アシル化反応によるペプチド合成法の開発 (2016)
  • Author(s): 田中啓太郎、田上兼輔、今村和也、小田稜子、橋本峻志、松尾綾香、山口泰史
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-03-26
• [Presentation] 失敗と困難から学ぶ創薬研究：Once upon a time in Switzerland and America. (2015)
  • Author(s): 山口泰史
  • Organizer: 日産化学 創薬セミナー
  • Place of Presentation: 日産化学 物質科学研究所、千葉県船橋市
  • Year and Date: 2015-06-18
  • Invited
• [Presentation] NaIによるアシル化剤活性化機構を利用した反応開発 (2015)
  • Author(s): 田中啓太郎 、田中誠一、山口泰史
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] アミノアルコールを含むジペプチドの合成 (2014)
  • Author(s): 田中啓太郎、田中誠一、梶原宏恵、加茂章弘、東叶奈、山口泰史
  • Organizer: 第31会日本薬学会九州支部大会
  • Place of Presentation: 福岡県福岡市、第一薬科大学
  • Year and Date: 2014-12-06 – 2014-12-07
• [Presentation] プロジェクトから考える創薬研究：Es war einmal in Basel, La Jolla und Connecticut (2014)
  • Author(s): 山口 泰史
  • Organizer: 第72回講演会有機化学研究会（白鷺セミナー）
  • Place of Presentation: 大阪府大阪市、大阪府立大学
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] 分子内アシル転位を利用したペプチド合成 (2014)
  • Author(s): 田中 啓太郎、田中 誠一、山口 泰史
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本県熊本市
• [Presentation] High affinity fluorescent probe for Zn2+ based on bipyridine scaffold (2014)
  • Author(s): Masayori Hagimoria, Naoko Mizuyamab, Yasuchika Yamaguchic, Hideo Sajid, Takahiro Mukai
  • Organizer: World Molecular Imaging Congress, 2014
  • Place of Presentation: South Korea, Seoul
• [Presentation] Activation of acyl group with sodium iodide (2013)
  • Author(s): Keitaro Tanaka, Masayori Hagimori, Yasuchika Yamaguchi
  • Organizer: The 23rd French-Japanese Symposium on Medicinal and Fine Chemistry (Nagasaki)
  • Place of Presentation: Nagasaki
• [Presentation] 生体内亜鉛イオンのイメージングを目的とした低分子量蛍光プローブの開発 (2013)
  • Author(s): 萩森政頼、水山奈央子、向 高弘、山口泰史、富永義則、佐治英郎
  • Organizer: 第24回日本微量元素学会学術集会
  • Place of Presentation: 大阪府吹田市
• [Presentation] NaIを用いたアシル化剤活性化の検討 (2013)
  • Author(s): 田中 啓太郎、田中 誠一、萩森 政頼、山口 泰史
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 長崎県佐世保市
• [Presentation] 亜鉛輸送体ZIP14の細胞内輸送および機能発現制御に関する基礎的解析 (2013)
  • Author(s): 大久保 麻佳、楢崎 彩香、萩森 政頼、山口 泰史、 藤井 佑樹、藤原 俊幸、徳永 研三、藤田 英明
  • Organizer: 第30回日本薬学会九州支部大会
  • Place of Presentation: 長崎県佐世保市
• [Presentation] 体験から考える創薬化学：Es war einmal in Basel, La Jolla und Connecticut (2013)
  • Author(s): 山口 泰史
  • Organizer: アステラス製薬・創薬セミナー
  • Place of Presentation: 茨城県つくば市
  • Invited
• [Presentation] 降圧薬プロジェクトから考える創薬研究 (2013)
  • Author(s): 山口泰史
  • Organizer: SYMPOSIUM2013 公開記念シンポジウム 創薬研究の潮流
  • Place of Presentation: 福岡
  • Invited
• [Presentation] NaIによるアシル化剤活性化 (2013)
  • Author(s): 田中啓太郎、萩森政頼、山口泰史
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
• [Presentation] Zn2+ Selective Fluorescent Probe Based on the Bipyridine Scaffold for Biological Applications (2012)
  • Author(s): Masayori HAGIMORI, Naoko MIZUYAMA, Takahiro MUKAI, Yasuchika YAMAGUCHI, Yoshinori TOMINAGA, and Hideo SAJI
  • Organizer: 第22回金属の関与する生体関連反応シンポジウム（SRM2012）
  • Place of Presentation: 金沢
• [Presentation] ルイス酸フリーのFriedel-Craftsアシル化反応の開発 (2012)
  • Author(s): 濱崎 翔平、萩森 政頼、田中 啓太郎、山口 泰史
  • Organizer: 第49回化学関連支部合同九州大会
  • Place of Presentation: 小倉
• [Presentation] 亜鉛イオンに対して高親和性を有する低分子量蛍光プローブの開発 (2012)
  • Author(s): 萩森政頼、水山奈央子、天滿敬、向高弘、山口泰史、富永義則、佐治英朗
  • Organizer: 第10回次世代を担う若手のためのフィジカル・ファーマフォーラム
  • Place of Presentation: 京都
• [Book] 新有機医薬品合成化学 (2012)
  • Author(s): 青柳榮、川﨑知己、小林 進、田口武夫、長坂達夫、東山公男、堀江利治、松本隆司、宮岡宏明、山口泰史
  • Total Pages: 355
  • Publisher: 廣川書店