| Project/Area Number |
10044327
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
KISO Yoshiaki Kyoto Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40089107)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Tooru Kyoto Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (70204980)
FUJIWARA Yoichi Kyoto Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (60199396)
HAYASHI Yoshio Kyoto Pharmaceutical University, Faculty of Pharmaceutical Sciences, Lecturer, 薬学部, 講師
YAMAZAKI Toshimasa Ministry of Agriculture, National Institute of Agriculture, National Institute of Agrobiological Resources Chief Researcher, 農業生物資源研究所, 主任研究官
KOBAYASHI Yuji Osaka University , Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20127228)
赤路 健一 京都薬科大学, 薬学部, 助教授 (60142296)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 1999: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1998: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | HIV protease inhibitor / Molecular Recognition / AIDS Therapeutics / Substrate Transition State / Double Drug / Peptide Synthesis / Enzyme Inhibitor / Anti-HIV Activity / ペプチドミメティック / 抗ウイルス薬 / ドラッグデザイン / 薬剤耐性 / 酵素・阻害剤複合体 |
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| Research Abstract |
Based on the substrate transition state concept of HIV protease, we have designed and synthesized HIV protease inhibitors containing hydroxymethylcarbony (HMC) isostere. Among them, a tripeptide derivative KNI-272 exhibited high selectivity, potent HIV protease inhibition, and high in vivo antiviral activity. NMR and molecular modeling studies showed that the HMC group interacts favorable with HIV protease active site and that the HMC isostere is an ideal transition state mimic.
The HIV protease inhibitors currently used for therapeutics need high dose and thus cause various side effects. Furthermore, HIV protease inhibitors induce mutation in the amino acid sequence of HIV-1 protease and decreased sensitivity, although HIV protease inhibitors have been considered as low mutation inducer because they attack the enzyme active center.
Therefore, we started the design and synthesis of low molecular weight HIV protease inhibitors. The small and potent inhibitors may be favorable in terms of the cost, resistance induction, pharmacokinetics and administration dose.
Taking into consideration of these factors, based on the molecular recognition between the enzyme and inhibitors, we designed small-sized highly-potent HIV protease inhibitors containing HMC isostere, and found the possibility to overcome the resistance and side effects. Furthermore, we synthesized prodrug-type conjugates of dipeptide HIV protease inhibitors with a reverse transcriptase inhibitors. We found that these new type of anti-HIV drugs showed excellent cell membrane permeability and synergistic effect, and proposed "Double-Drug" concept.
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