1999 Fiscal Year Final Research Report Summary
Molecular design of HIV protease inhibitors restricted to active conformation
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 |
Section | 展開研究 |
Research Field |
医薬分子機能学
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Research Institution | KYOTO PHARMACEUTICAL UNIVERSITY |
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)
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Project Period (FY) |
1997 – 1999
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Keywords | HIV protease / Molecular Recognition / AIDS Therapeutics / Substrate Transition State / HIV Protease Inhibitor / Peptide Synthesis / Enzyme Inhibitor / Anti-HIV Activity |
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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Research Products
(13 results)
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[Publications] Tsutomu Mimoto, Ryohei Kato, Haruo Takaku, Satoshi Nojima, Keisuke Terashima, Satoru Misawa, Tominaga Fukazawa, Takamasa Ueno, Hideharu Sato, Makoto Shintani, Yoshiaki Kiso, and Hideya Hayashi: "Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine."J.Med.Chem.. 42(10). 1789-1802 (1999)
Description
「研究成果報告書概要(欧文)」より
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