| Project/Area Number |
12557218
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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 UNIVERSITY |
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Principal Investigator |
FUJII Nobutaka Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (60109014)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Naoki Tokyo Medical and Dental University, School of Medicine, Professor, 医学部, 教授 (00094053)
TAMAMURA Hirokazu Kyoto University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 講師 (80217182)
OTAKA Akira Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (20201973)
黒川 勉 武田薬品工業, 戦略研究室, 室長
西村 紀 島津製作所, 部長(リサーチフェロー)
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| Project Period (FY) |
2000 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | anti-HIV agents / chemokine receptor / T-cell line-tropic HIV / T140 / low molecular weight CXCR4 antagonists / HIV-cell fusion inhibitors / de novo design / de novo分子設計 / CXCR4アンタゴニスト / HIV侵入阻害剤 / T細胞指向性HIV-1 / de novo設計 / 環状ペプチド / 環状ペンタペプチドライブラリー / ホモロジーモデリング / 機能性CXCR4変異体 / T140-CXCR4ドッキング解析 / FC131 / gp41-標的型HIV-Cell膜融合阻害剤 / SC34EK / spring8 / CXCR4拮抗剤 / HIVプロテアーゼ阻害剤 / HIV-cell融合阻害剤 / 多剤耐性克服型抗HIV剤 / 二価官能性抗HIV剤 / gp41 / HIV第二受容体拮抗剤 / CXCR4ケモカイン受容体 / T140立体構造 / 逆転写酵素阻害 / エイス / コンビナトリアル合成 / 有用金属試薬 |
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| Research Abstract |
We have developed two types of anti-HIV agents, which target dynamic supra-molecular mechanism involved in HIV-cell fusion: One is co-receptor (CXCR4) antagonists, such as T140 analogs. The other is fusion inhibitors based on C34, a gp41-derived 34-mer peptide fragment, such as SC34.
(1)An anti-HIV peptide, T140, was found to inhibit the entry of X4-HIV-1 (T cell line-tropic HIV) through its specific binding to a chemokine receptor, CXCR4, which is functioned as the co-receptor for the X4-HIV entry.
a) A cyclic pentapeptide library was adopted to dispose the side-chains of the indispensable T140 residues in proximity. This focused library led to discovery' of potent cyclic pentapeptides.
b) A novel pharmacophore was found in the N-terminal region of T140. Based on the enhancement of T140-derived pharmacophores other low molecular weight CXCR4 antagonists were designed and synthesized.
b) A novel pharmacophore was found in the N-terminal region of T140. Based on the enhancement of T140-derived pharmacophores other low molecular weight CXCR4 antagonists were designed and synthesized.
2) De novo design based on C34 led to development of a synthetic peptide, SC34, which has several advantages as a potential candidate for gp41-target HIV-cell fusion inhibitors (high solubility, enhanced anti-HIV activity, effectiveness against a T20 [Fuzeon]-resistant strain).
These results are thoughtt to be useful for the structure-based drug design of anti-HIV agents.
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