Development of a novel persistent protease inhibitor containing D-amino acid

• Project/Area Number: 21590017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Kyoto Pharmaceutical University (2011); Kyoto Prefectural University of Medicine (2009-2010)
• Principal Investigator: AKAJI Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
• Co-Investigator(Renkei-kenkyūsha): NOSAKA Kazuto 兵庫医科大学, 医学部, 教授 (10228314) ; KONNO Hiroyuki 山形大学, 大学院・理工学研究科, 准教授 (50325247)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: SARS / HTLV-1 / プロテアーゼ阻害剤 / 構造解析 / Dアミノ酸 / Retro-Inverso / プロテアーゼ / 阻害剤

Research Abstract

Effects of Retro-Inverso(RI) modifications of HTLV-1 protease inhibitors containing ahydroxyethylamine isoster backbone were clarified. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RIinhibitors would interact with HTLV-1 protease in the same manner as the parenthydroxyethylamine inhibitor. The design and evaluation of low-molecular weight peptide-based SARS 3CL protease inhibitors are also clarified. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P3 site directed toward the outside of the protease.

Research Products

• [Journal Article] Structure-based Design, Synthesis, and Evaluation of Peptide-mimetic SARS 3CL Protease Inhibitors (2011)
  • Author(s): Akaji, K.; Konno, H.; Mitsui, H.; Teruya, K.; Shimamoto, Y.; Hattori, Y.; Ozaki, T.; Kusunoki, M.; Sanjoh, A
  • Journal Title: J. Med. Chem Volume: 54 Pages: 7962-7937
  • Peer Reviewed
• [Journal Article] Synthesis of Tokaramide A, a Cysteine Protease Inhibitor from Marine Sponge Theonella aff (2011)
  • Author(s): Konno, H.; Nosaka, K.; Akaji, K
  • Journal Title: Mirabilis. Tetrahedron Volume: 67 Pages: 9067-9071
• [Journal Article] Structure-Based Design, Synthesis, and Evaluation of Peptide-Mimetic SARS 3CL Protease Inhibitors (2011)
  • Author(s): Kenichi. Akaji, et.al.
  • Journal Title: J.Med.Chem. Volume: 54 Issue: 23 Pages: 7962-7973
  • DOI: 10.1021/jm200870n
  • Peer Reviewed
• [Journal Article] Synthesis of solamin type mono-THF acetogenins using cross-methathesis (2010)
  • Author(s): Konno, H.; Makabe, H.; Hattori, Y.; Nosaka, K.; Akaji, K
  • Journal Title: Tetrahedoron Volume: 66 Pages: 7946-7953
  • Peer Reviewed
• [Journal Article] Synthetic studies on callipeltins : Stereoselective syntheses of(3S, 4R)-3, 4-Dimethyl-L-pyroglutamic acid and Fmoc-D-allothreonine from serine derivatives (2010)
  • Author(s): Konno, K.; Takebayashi, Y.; Nosaka, K.; Akaji, K
  • Journal Title: Heterocycles Volume: 81 Pages: 79-89
  • NAID: 40016913697
  • Peer Reviewed
• [Journal Article] Evaluation of retero-inverso modification of HTLV-1 protease inhibitors containing a hydroxylethyl amine isoster (2010)
  • Author(s): Tatsumi, T.; Awahara, C.; Naka, H.; Aimoto, S.; Konno, K.; Nosaka, K.; Akaji, K
  • Journal Title: Bioorg Med. Chem Volume: 18 Pages: 2720-2727
  • Peer Reviewed
• [Journal Article] Evaluation of retero-inverso modification of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster (2010)
  • Author(s): Tatsumi, T.; Awahara, C.; Naka, H.; Aimoto, S.; Konno, K.; Nosaka, K.; Akaji, K
  • Journal Title: Bioorg.Med.Chem Volume: 18 Pages: 2720-2727
  • Peer Reviewed
• [Journal Article] Synthesis of solamin type mono-THF acetogenins using cross-methathesis (2010)
  • Author(s): Konno, H.; Makabe, H.; Hattori, Y.; Nosaka, K.; Akaji, K
  • Journal Title: Tetrahedron Volume: 66 Pages: 7946-7953
  • Peer Reviewed
• [Journal Article] Synthetic studies on callipeltins : Stereoselective syntheses of(3S,4R)-3,4-Dimethyl-L-pyroglutamic acid and Fmoc-D- allothreonine from serine derivatives (2010)
  • Author(s): Konno, K.; Takebayashi, Y.; Nosaka, K.; Akaji, K
  • Journal Title: Heterocycles Volume: 81 Pages: 79-89
  • NAID: 40016913697
  • Peer Reviewed
• [Journal Article] Synthesis of [19, 35, 36-13C3]-labeled TAK779 as a Molecular Probe. (2009)
  • Author(s): Konno H, ; Aimoto S, ; Smith SO, ; Nosaka K, ; Akaji K
  • Journal Title: Bioorg Med. Chem Volume: 17 Pages: 5769-5774
  • Peer Reviewed
• [Journal Article] Synthesis of [19,35,36-13C3]-labeled TAK779 as a Molecular Probe (2009)
  • Author(s): Konno H, Aimoto S, Smith S.O, Nosaka K, Akaji K
  • Journal Title: Bioorg.Med.Chem 17 Pages: 5769-5774
  • Peer Reviewed
• [Presentation] Design, synthesis, and evaluation of tripeptidemimetics with aryl ketone as inhibitors of SARS-COV 3CL protease (2011)
  • Author(s): Kenichi Akaji, et.al.
  • Organizer: 48^<th> Japanese peptide symposium
  • Place of Presentation: 札幌コンベンションセンター(札幌市)
  • Year and Date: 2011-09-28
• [Presentation] Evaluation of substrate specificities for BACE 1 using synthetic peptide libraries (2010)
  • Author(s): T Kakizawa, Y Hattrori, K Teruya, A Sanjoh2, K Akaji
  • Organizer: 第5回国際ペプチドシンポジウム
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-12-05
• [Presentation] Synthesis and Evaluation of Small PeptideInhibitors for SARS 3CL Protease (2010)
  • Author(s): Hiroyuki Konno, Manabu Ishii, Yasunao Hattori, Kazuto Nosaka, Kenichi Akaji
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto, Japan
• [Presentation] 構造解析に基づくSARS 3CL Protease阻害剤の設計とその阻害能評価 (2010)
  • Author(s): 今野博行、石井学、野坂和人、服部恭尚、赤路健一
  • Organizer: 東北支部第145回大会
  • Place of Presentation: 仙台
• [Presentation] SARS 3CLプロテアーゼ阻害剤創成を目指したペプチドアルデヒドの合成と阻害能評価 (2010)
  • Author(s): 今野博行、石井学、服部恭尚、野坂和人、赤路健一
  • Organizer: 日本農芸化学会大会
  • Place of Presentation: 東京
• [Presentation] 構造解析に基づくペプチドアルデヒド型SARS 3CLプロテアーゼ阻害剤の合成と評価 (2009)
  • Author(s): 今野博行、野坂和人、小野塚真理、三井寛典、赤路健一、楠木正巳、尾崎健、三城明
  • Organizer: 第35回反応と合成の進歩シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2009-11-16
• [Presentation] Design of small molecular inhibitor for SARS 3CL protease besed on structure analysis (2009)
  • Author(s): Akaji K, Nosaka K, Hattori Y, Mitsui H, Konno H, Kusunoki M, Ozaki T, Sanjo A
  • Organizer: 第46回ペプチド討論会
  • Place of Presentation: 北九州
  • Year and Date: 2009-11-04
• [Presentation] 固相法によるペプチドアルデヒド類の実践的合成法の検討 (2009)
  • Author(s): 今野博行、石井学、服部恭尚、野坂和人、赤路健一
  • Organizer: 第46回ペプチド討論会
  • Place of Presentation: 北九州
  • Year and Date: 2009-11-04
• [Presentation] SARS 3CLプロテアーゼ阻害に必要なチオール反応性官能基の評価 (2009)
  • Author(s): 三井寛法、高橋麻矢子、今野博行、野坂和人、赤路健一
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Remarks]
  • URL: http://www.kyoto-phu.ac.jp/labo/yakuhin/
• [Remarks]
  • URL: http://www.kyoto-phu.ac.jp/labo/yakuhin/
• [Remarks]
  • URL: http://www.f.kpu-m.ac.jp/Y/chem/
• [Remarks]
  • URL: http://www.f.kpu-m.ac.jp/y/chem/