Design of pseudo-symmetric protease inhibitors setting hydrogenbonding bridging water molecules

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790121
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: HIDAKA Koushi Kyoto Pharmaceutical University, 薬学部, 助教 (30445960)
• Project Period (FY): 2009 – 2010
• Keywords: 感染症 / 酵素 / 阻害剤 / 分子設計 / 分子認識 / アスパラギン酸プロテアーゼ / HIVプロテアーゼ / プラスメプシン / 架橋水

Research Abstract

Pseudo-symmetric protease inhibitors which have unique "HMC-hyrazide" as a transition state mimic to set multiple bridging waters were designed. Although the synthetic pseudo-symmetric compounds exhibited some reduction of inhibitory activity against multi-mutated HIV protease, the activity reduction of derivatives with oxamide at both terminals were relatively less. The pseudo-symmetric compounds also exhibited HTLV-I protease inhibitory activity.

Research Products

• [Journal Article] Crystal Growth Procedure of HIV-1Protease-Inhibitor KNI-272 Complex for Neutron Structural Analysis at 1.9 A Resolution. (2010)
  • Author(s): (1)Noriko Shimizu, Shigeru Sugiyama, Mihoko Maruyama, Yoshinori Takahashi, Motoyasu Adachi, Taro Tamada, Koushi Hidaka, Yoshio Hayashi, Tooru Kimura, Yoshiaki Kiso, Hiroaki Adachi, Kazufumi Takano, Satoshi Murakami, Tsuyoshi Inoue, Ryota Kuroki, Yusuke Mori Hiroyoshi Matsumura
  • Journal Title: Crystal Growth & Design 10(7) Pages: 2290-2294
  • Peer Reviewed
• [Journal Article] How much binding affinity can be gained by filling a cavity? (2010)
  • Author(s): Yuko Kawasaki, Eduardo E. Chufan, Virginie Lafont, Koushi Hidaka, Yoshiaki Kiso, Mario Amzel, Ernesto Freire
  • Journal Title: Chem.Biol.Drug Design 75(2) Pages: 143-151
  • Peer Reviewed
• [Journal Article] Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S_2' pocket. (2009)
  • Author(s): Koushi Hidaka, Tooru Kimura, Hamdy M.Abdel-Rahman, Jeffrey-Tri Nguyen, Keith F.McDaniel, William E. ohlbrenner, Akhteruzzaman Molla, Motoyasu Adachi, Taro Tamada, Ryota Kuroki, Noriko Katsuki, Yoshiaki Tanaka, Hikaru Matsumoto, Jun Wang, Yoshio Hayashi, Dale J. Kempf Yoshiaki Kiso.
  • Journal Title: J.Med.Chem. 52(23) Pages: 7604-7617
  • Peer Reviewed
• [Presentation] 薬剤耐性変異を導入したHIV プロテアーゼを標的とする擬似対称型阻害剤の構造活性相関研究 (2011)
  • Author(s): 戸田侑紀, 日高興士, 濱田貴司, 木曽良明
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: ツインメッセ静岡(静岡)
  • Year and Date: 20110300
• [Presentation] ロピナビル耐性株由来の変異を導入したHIV プロテアーゼ誘導体の解析 (2010)
  • Author(s): 日高興士, 安達基泰, 黒木良太, 濱田貴司, Rajesh Sankaranarayanan, 木村徹, 木曽良明
  • Organizer: 第24回日本エイズ学会学術集会
  • Place of Presentation: 高輪グランドプリンスホテル(東京)
  • Year and Date: 20101100
• [Presentation] ロピナビル耐性株由来のHIV プロテアーゼ変異体とアロフェニルノルスタチン阻害剤の相互作用解析 (2010)
  • Author(s): 日高興士, 安達基泰, 黒木良太, 濱田貴司, Rajesh Sankaranarayanan, 木村徹, 木曽良明
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都テルサ(京都)
  • Year and Date: 20101100
• [Presentation] ロピナビル耐性を獲得した変異HIV プロテアーゼに対するアロフェニルノルスタチン阻害剤の活性評価 (2010)
  • Author(s): 日高興士, 安達基泰, 黒木良太, 濱田貴司, Rajesh Sankaranarayanan, 木村徹, 木曽良明:
  • Organizer: 第24回近畿エイズ研究会学術集会
  • Place of Presentation: 大阪市立総合医療センター(大阪)
  • Year and Date: 20100600
• [Presentation] 架橋水および水和を利用するHIV プロテアーゼ阻害剤研究 (2009)
  • Author(s): 日高興士, Jeffrey-Tri Nguyen, 濱田貴司, 安達基泰, 黒木良太, 木村徹, 木曽良明
  • Organizer: 第23回日本エイズ学会学術集会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 20091100
• [Presentation] アロフェニルノルスタチンを骨格とする感染症治療薬設計。若手研究者シンポジウム, 次世代創薬 (2009)
  • Author(s): 日高興士
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京大学山上会館(東京)
  • Year and Date: 20091100
• [Presentation] HIV protease inhibitor design to employ water molecules.Sixth General Meeting of the International Proteolysis Society (2009)
  • Author(s): Koushi Hidaka, T.Hamada, M.Adachi, R.Kuroki, T.Kimura, Y.Kiso
  • Organizer: Surfers Paradise Marriott Resort & Spa
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 20091000
• [Remarks] ホームページ等
  • URL: http://www.kyoto-phu.ac.jp/labo/yakuhin/publicns.html