| Project/Area Number |
08044325
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Chemical pharmacy
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| Research Institution | KYOTO PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
KISO Yoshiaki Kyoto Pharmaceutical Sciences, Professor, 薬学部, 教授 (40089107)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Toshimasa Ministry of Agriculture, National Institute of Agrobiological Resources, Chief R, 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)
KIMURA Tooru Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (70204980)
FUJIWARA Yoichi Faculty of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (60199396)
AKAJI Kenichi Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60142296)
USSERY Micha Division of Antiviral Drug Products, U. S., Director
TORCHIA Denn National Institute of Dental Research, NI, Chief
YARCHOAN Rob National Cancer Institute, NIH, Chief
満屋 裕明 National Cancer Institute, NIH, Chief
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥11,600,000 (Direct Cost: ¥11,600,000)
Fiscal Year 1997: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 1996: ¥5,800,000 (Direct Cost: ¥5,800,000)
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| Keywords | HIV Protease / Molecular Recognition / AIDS Therapeutics / Substrate Transition State / HIV Protease Inhibitor / Peptide Synthesis / Enzyme Inhibitor / Anti-HIV Activity |
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| Research Abstract |
We have designed and synthesized a highly selective and potent HIV protease inhibitor (KNI-272) based on the substrate transition state concept of HIV protease. KNI-272 exhibits low cytotoxicity, specifically interacts with the HIV protease active site, because it was rationally designed based on the reaction mechanism of HIV protease, and thus is expected to be an ideal anti-AIDS drug. Therefore, starting from these results, the analysis of the interaction of KNI-272 with HIV protease showed that KNI-272 has constrained conformation and is an ideal transition state mimic.
Furthermore, we carried out the molecular structural analysis of mutant HIV protease and rationally designed a series of new anti-HIV drugs based on the interaction between mutant enzyme and inhibitors.
In the mutant HIV and HIV-2, their HIV protease have low enzymatic activity. Furthermore, it is reported that mutant HIV exhibits low infectivity and HIV-2 has low pathogenicity. These facts implies that low enzymatic activity is one of the causes of low infectivity. We made approach at chemical structure level of enzymes to molecular mechanism analysis of viral pathogenicity. As a result, we have found small sized dipeptide HIV protease inhibitors, KNI-413 and KNI-549. In addition, we designed KNI-241 and smaller-sized KNI-727 which are active against HIV-1 resistant to KNI-272.
This research on HIV protease inhibitors was rationally carried out based on the structural analysis of the complex of the enzyme and the inhibitor, and is regarded to establish the methodology to control the drug resistance of HIV.
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