| Project/Area Number |
15590030
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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 |
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Principal Investigator |
KIMURA Tooru Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Research Associate, 薬学部, 助手 (70204980)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Chemical Ligation / Protease / Solid Phase Peptide Synthesis / HTLV / HAM / ATL |
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| Research Abstract |
HTLV-I is a virus similar as HIV and causative agent for adult T-cell leukemia (ATL) and HTLV-I associated myelopathy (HAM). HTLV-I encodes a virus-specific aspartic protease and the inhibitors are expected as drugs for these disease. Aim of this project is synthesis of HTLV-I protease analog in order to utilize for development of the inhibitor. The synthesis of HTLV-I protease analog was achieved by a sulfide forming chemical ligation method using a thiol and an alkyl halide, which was successfully applied for the synthesis of HIV-I protease analog. The evaluation system for inhibitors was also established.
At first, we designed a new mercaptoamide-resin applicable to standard solid phase peptide synthesis. A mercaptoamide-peptide segment prepared using this new resin and a bromoacetylated peptide synthesized conventionally were applied for the chemical ligation and an homogeneous HTLV-I protease analog was obtained easy.
Next, the enzymatic activity of the HTLV-I protease analog was measured using a synthetic substrate peptide. The activity of the analog was comparable to the reported values of native enzyme.
The activities of inhibitors prepared as other aspartic proteases inhibitors were determined using the HTLV-I protease analog and a synthetic substrate. However, all compounds showed weak inhibitory activity against HTLV-I protease. In order to obtain potent inhibitors of HTLV-I protease, new design seems to be necessary and our evaluation system using synthetic HTLV-I protease analog is useful for this purpose.
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