| Project/Area Number |
07308067
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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 | 総合 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
KISO Yoshiaki Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Professor, 薬学部, 助教授 (40089107)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Tooru Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Assistant, 薬学部, 助手 (70204980)
FUJIWARA Yoichi Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Assistant, 薬学部, 助手 (60199396)
AKAJI Kenichi Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Associate P, 薬学部, 助教授 (60142296)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1996: ¥4,000,000 (Direct Cost: ¥4,000,000)
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| Keywords | HIV Protease Inhibitors / Enzyme・Inhibitor Complex / Substrate Transition State Analog / Peptide synthesis / Conformational Analysis / X-ray Crystallography / Drug Resistant Virus / Anti-AIDS Drug / コンフォメーション解析 / コンフォーメーション解析 |
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| Research Abstract |
Based on the substrate-transition state concept, we have succeeded to design and synthesize a highly selective and potent HIV protease inhibitor (KNI-272). Since KNI-272 was rationally designed based on the action mechanism of HIV protease, it exhibits low cytotoxicity and interacts selectively with HIV protease active site. These results strongly attracted the attention of the Directro of National Cancer Institute, U.S.A., and we have already started research collaboration with a research group there.
In order to make a further progress of our research, we carried out the molecular structural analysis of mutant viruses and anti-AIDS drug complexed with mutant enzymes, and rationally designed novel anti-AIDS drugs considering the drug-enzyme interactions. The results of our research are highly expected as the strategy against resistant HIV.The compounds obtained by our research are considered as promising anti-AIDS drugs to overcome side effect and resistance.
KNI-272-insensitive virus strains were identified. Based on the amino acid sequence, the mutated proteases were synthesized by genetic engineering or chemical methods. We analyzed the interaction between mutant enzymes and anti-AIDS drugs and examined the active conformation of the drugs. Potent inhibitors such as KNI-272 were shown to have highly constrained conformation by x-ray crystallography, NMR and molecular modeling.
Furthermore, based on the analysis of enzyme-inhibitor interaction, we have analyzed the essential functional groups of the inhibitor participating in the interaction. We designed and synthesized HIV protease inhibitors aiming at ideal anti-AIDS drugs without resistance and side effects. Dipeptide derivatives with high HIV protease inhibiting activity were obtained.
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