| Project/Area Number |
05671871
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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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 Univ., Fac.Pharm.Sci., Professor, 薬学部, 教授 (60109014)
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| Co-Investigator(Kenkyū-buntansha) |
TAMAMURA Hirokazu Kyoto Univ., Fac.Pharm.Sci., Assistant Professor, 薬学部, 助手 (80217182)
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| Project Period (FY) |
1993 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | anti-HIV activity / tachyplesin / polyphemusin / T22 / beta-sheet / T cell / AgOTf-DMSO / HCI / solution-phase synthesis / AgOTf / DMSO / NMR / β-sheet |
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| Research Abstract |
We found a novel anti-HIV peptide, T22, through a structure-activity relationship study on horseshoe crab antimicrobial peptides, tachyplesin and polyphemusin. In order to elucidate the action mechanisms of T22, and to develop new anti-HIV agents based on T22, we carried out the following investigations.
1.Conformatinal analysis of T22
The secondary structure of T22 was confirmed to be similar to that of tachyplesin I using NMR.The antiparallel beta-sheet structure and the several amino acid chains of the beta-sheet plane of T22 are though to be associated with the expression of anti-HIV activity.
2.Action mode of T22
We investigated molecular paramenters necessary for the expression of the strong anti-HIV activity of T22. The results suggest that the anti-HIV activity of T22 is mediated through the interaction with chiral component (s) of the cell or virus, and that there is a positive correlation between cytotoxicity and membrane permeability. Furthermore we found that T22 binds to T cel
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l surfaces, and that there is a positive correlation between binding activity and anti-HIV activity. In addition, a binding site on the T22 peptide was idetified.
3.Solution-phase synthesis of T22
The synthetic method of T22 on a large scale using solution-phase techniques was established in order to provide sufficient materials for mechanical and preclinical studies.
4.Development of a regioselective disulfide bond-forming method
A regioselective disulfide bond-forming method using the AgOTf-DMSO/HCl system was developed in order to facilitate the unambiguous synthesis of the two-disulfide and Trp containing peptides, such as T22 analogs.
5.Structure-activity relationshipt of T22
Using the above regioselective disulfide bond-forming method, several T22 analogs were synthesized and provided for the structure-activity relationship study in order to define the active site and cytotoxic site of T22.
These findings will lead to the development of new types of anti-AIDS drugs with novel mechanisms of action. Less
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