Development of pseudo-symmetric inhibitors targeted HIV and HTLVproteases

• Project/Area Number: 23790145
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kobe Gakuin University
• Principal Investigator: HIDAKA Koushi 神戸学院大学, 薬学部, 講師 (30445960)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 医薬分子設計 / 分子設計 / 酵素 / 阻害剤 / HIVプロテアーゼ / HTLV-Iプロテアーゼ / 擬似対称型阻害剤 / 成人T細胞白血病 / HTLV-I脊髄症

Research Abstract

Application of HIV protease inhibitors developed from substrate amino acid sequence to designing method of pseudo-symmetric inhibitors using “HMC-hydrazide” succeeded in obtaining new and potent inhibitors. We confirmed the position of five bridging water molecules in the complex by X-ray crystallography. We explored substituents at the terminals of the inhibitor to find effective compounds for drug resistant mutant protease. We also obtained potent substrate-based HTLV protease inhibitors, which are promising to apply for the pseudo-symmetric inhibitor design.

Research Products

• [Journal Article] Oxamide replacement in pseudo-symmetric HIV protease inhibitor involving multiple bridging water molecules. (2013)
  • Author(s): Koushi Hidaka, Yuki Toda, Yuko Tsuda, and Yoshiaki Kiso
  • Journal Title: Peptide Science,2012 49th Pages: 271-272
  • NAID: 10031161625
  • URL: http://www.prf.or.jp/psb.html
  • Peer Reviewed
• [Journal Article] Use of substituted oxamide structure in designing pseudo-symmetric HIV protease inhibitors to employ multiple bridging water molecules. (2013)
  • Author(s): Koushi Hidaka, Yuki Toda, Motoyasu Adachi, Ryota Kuroki, Yoshiaki Kiso
  • Journal Title: PEPTIDES 2012 Pages: 404-405
  • URL: http://www.eurpepsoc.com/symposia-proceedings/
• [Journal Article] Use of substituted oxamide structure in designing pseudo- symmetric HIV protease inhibitors to employ multiple bridging water molecules. (2013)
  • Author(s): Koushi Hidaka
  • Journal Title: PEPTIDES 2012 Volume: 32 Pages: 404-405
• [Journal Article] Oxamide replacement in pseudo-symmetric HIV protease inhibitor involving multiple bridging water molecules. (2013)
  • Author(s): Koushi Hidaka
  • Journal Title: Peptide Science 2012 Volume: 49 Pages: 271-272
  • NAID: 10031161625
  • Peer Reviewed
• [Journal Article] ペプチド化学を基盤とした統合創薬科学 (2012)
  • Author(s): 木曽良明,日高興士
  • Journal Title: 化学工業 Volume: 63(4) Pages: 258-263
  • URL: http://www.kako-sha.co.jp/kagakubacknoright.htm
• [Journal Article] Maintaining potent HTLV-I protease inhibition without the P3-cap moiety in small tetrapeptidic inhibitors. (2011)
  • Author(s): Jeffrey-Tri Nguyen, Keiko Kato, Henri-Obadja Kumada, Koushi Hidaka, Tooru Kimura, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 21 Issue: 6 Pages: 1832-1837
  • DOI: 10.1016/j.bmcl.2011.01.048
  • Peer Reviewed
• [Journal Article] Design and synthesis of several small-size HTLV-I protease inhibitors with different hydrophilicity profiles. (2011)
  • Author(s): Jeffrey-Tri Nguyen, Keiko Kato, Koushi Hidaka, Henri-Obadja Kumada, Tooru Kimura, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 21 Issue: 8 Pages: 2425-2429
  • DOI: 10.1016/j.bmcl.2011.02.066
  • Peer Reviewed
• [Journal Article] Development of L40I HTLV-I protease inhibition assay using novel fluorogenic and chromogenic substrate. (2011)
  • Author(s): Henri-Obadja Kumada, Jeffrey-Tri Nguyen, Keiji Nishiyama, Taeko Kakizawa, Yasuhiro Arii, Koushi Hidaka, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: J. Peptide Science Volume: 17(8) Issue: 8 Pages: 569-575
  • DOI: 10.1002/psc.1375
  • Peer Reviewed
• [Presentation] Use of substituted oxamide structure in designing pseudo-symmetric HIV protease inhibitors to employ multiple bridging water molecules (2012)
  • Author(s): Koushi Hidaka, Yuki Toda, Motoyasu Adachi, Ryota Kuroki, Yoshiaki Kiso
  • Organizer: 32th European Peptide Symposium
  • Place of Presentation: Athens, Greece
  • Year and Date: 2012-09-27
• [Presentation] Oxamide replacement in pseudo-symmetric HIV protease inhibitor involving multiple bridging water molecules (2012)
  • Author(s): Koushi Hidaka, Yuki Toda, Yuko Tsuda, and Yoshiaki Kiso
  • Organizer: 49th Japanese Peptide Symposium
  • Place of Presentation: Kagoshima, Japan
• [Presentation] 複数の架橋水を配置する擬似対称型HIVプロテアーゼ阻害剤の設計 (2012)
  • Author(s): 日高興士,戸田侑紀,木曽良明
  • Organizer: 第26回日本エイズ学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Use of substituted oxamide structure in designing pseudo- symmetric HIV protease inhibitors to employ multiple bridging water molecules. (2012)
  • Author(s): Koushi Hidaka
  • Organizer: 32th European Peptide Symposium
  • Place of Presentation: Athens, Greece
• [Presentation] 多数の架橋水を伴う擬似対称型HIVプロテアーゼ阻害剤のオキサミド置換 (2012)
  • Author(s): 日高興士
  • Organizer: 第49回ペプチド討論会
  • Place of Presentation: 鹿児島
• [Presentation] 薬剤耐性変異HIVプロテアーゼを標的とする擬似対称型阻害剤研究 (2011)
  • Author(s): 戸田有紀,日高興士,濱田貴司,黒木良太,木曽良明
  • Organizer: 第25回近畿エイズ研究会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2011-06-18
• [Presentation] Takashi Hamada, Motoyasu Adachi, Ryota Kuroki, Yoshiaki Kiso: Design of multiple bridging water-assisted pseudo- symmetric HIV prptease inhibitors (2011)
  • Author(s): Koushi Hidaka, Yuki Toda
  • Organizer: 7th General Meeting of the International Proteolysis Society
  • Place of Presentation: San Diego, USA
• [Presentation] 薬剤耐性変異HIVプロテアーゼを標的とする擬似対称型阻害剤研究. (2011)
  • Author(s): 戸田有紀, 日高興士, 濱田貴司, 黒木良太, 木曽良明
  • Organizer: 第25回近畿エイズ研究会学術集会
  • Place of Presentation: 京都
• [Presentation] Design of multiple bridging water-assisted pseudo-symmetric HIV prptease inhibitors. (2011)
  • Author(s): Koushi Hidaka, Yuki Toda, Takashi Hamada, Motoyasu Adachi, Ryota Kuroki, Yoshiaki Kiso
  • Organizer: 7th General Meeting of the International Proteolysis Society
  • Place of Presentation: San Diego, USA
• [Remarks]
  • URL: http://www.kobegakuin.ac.jp/information/public/teacher/pharmacy/hidaka.html
• [Remarks] 情報の公表 - 教員総覧（薬学部）
  • URL: http://www.kobegakuin.ac.jp/information/public/teacher/pharmacy/hidaka.html
• [Remarks]
  • URL: http://www.kobegakuin.ac.jp/general-information/soran/06_yakugaku/hidaka.html