2011 Fiscal Year Final Research Report
Development of a novel persistent protease inhibitor containing D-amino acid
| Project/Area Number |
21590017
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Kyoto Pharmaceutical University (2011)
Kyoto Prefectural University of Medicine (2009-2010) |
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Principal Investigator |
AKAJI Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
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| Co-Investigator(Renkei-kenkyūsha) |
NOSAKA Kazuto 兵庫医科大学, 医学部, 教授 (10228314)
KONNO Hiroyuki 山形大学, 大学院・理工学研究科, 准教授 (50325247)
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| Project Period (FY) |
2009 – 2011
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| Keywords | SARS / HTLV-1 / プロテアーゼ阻害剤 / 構造解析 / Dアミノ酸 / Retro-Inverso |
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| Research Abstract |
Effects of Retro-Inverso(RI) modifications of HTLV-1 protease inhibitors containing ahydroxyethylamine isoster backbone were clarified. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RIinhibitors would interact with HTLV-1 protease in the same manner as the parenthydroxyethylamine inhibitor. The design and evaluation of low-molecular weight peptide-based SARS 3CL protease inhibitors are also clarified. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P3 site directed toward the outside of the protease.
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[Journal Article] Structure-based Design, Synthesis, and Evaluation of Peptide-mimetic SARS 3CL Protease Inhibitors2011
Author(s)
Akaji, K.; Konno, H.; Mitsui, H.; Teruya, K.; Shimamoto, Y.; Hattori, Y.; Ozaki, T.; Kusunoki, M.; Sanjoh, A
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Journal Title
J. Med. Chem
Volume: 54
Pages: 7962-7937
Peer Reviewed
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