| Project/Area Number |
09557203
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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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)
藤原 洋一 京都薬科大学, 薬学部, 助手 (60199396)
三本 勤 株式会社ジャパンエナジー, 医薬バイオ研究所, 研究員
赤路 健一 京都薬科大学, 薬学部, 助教授 (60142296)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1997: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | HIV protease / Molecular Recognition / AIDS Therapeutics / Substrate Transition State / HIV Protease Inhibitor / Peptide Synthesis / Enzyme Inhibitor / Anti-HIV Activity / ペプチドミメティック / ドラッグデザイン / 薬剤耐性 / 酵素・阻害剤複合体 / 抗ウイルス薬 |
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| Research Abstract |
Introduction of HIV protease inhibitors with new action mechanism as anti-HIV drugs provided a new development in the combination therapy of AIDS. However, there are many problems to be solved such as dose, economics, side effects, resistance, transport to central nervous system.
In order to overcome these problems, we designed and synthesized small-sized HIV protease inhibitors containing hydroxymethlcarbonyl (HHMC) isostere, and ideal transition state mimic, based on the data obtained from NMR structural analysis and molecular modeling studies. Inhibitors of small size and high potency are advantageous in terms of cost, and resistance induction as well, because molecular recognition studies showed that these inhibitors interacts with the enzyme at fewer sites. Furthermore, smaller-sized inhibitors may exhibit better tissue transportation, improved pharmacokinetics and may be usable at lower dose. These results indicate that HMC-containing depicted inhibitors are promising for combination therapy as HIV protease inhibitors of next generation.
O-N Acyl migration-type prodrug of HIV protease inhibitors exhibited better solubility and improved bioavailability, which shows excellent cell membrane permeability and synergistic effect acting on the different targets in HIV replication by intracellularly generated components. This new hybrid type drugs are expected as a new type of resistance surmountable anti-AIDS agents.
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