Studies on the elucidantion of action mechanisms of tachyplesin analogs as anti-HIV peptides

鲎素类似物作为抗 HIV 肽作用机制的阐明研究

基本信息

批准号：
05671871
负责人：
FUJII Nobutaka
金额：
$ 1.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671871/
关键词：
anti-HIV activity tachyplesin polyphemusin T22 beta-sheet T cell AgOTf-DMSO HCI solution-phase synthesis AgOTf DMSO NMR β-sheet

项目摘要

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 T22The 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 T22We 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 … More 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 T22The 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 methodA 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 T22Using 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

我们通过对鲎抗菌肽、tachyplesin和polyphemusin的构效关系研究，发现了一种新型抗HIV肽T22，以阐明T22的作用机制，并开发基于T22的新型抗HIV药物。我们进行了以下研究。 1.T22的构象分析使用T22的二级结构证实T22与tachyplesin I的二级结构相似NMR。T22的反平行β-折叠结构和β-折叠平面的几个氨基酸链被认为与抗HIV活性的表达有关。2.T22的作用模式我们研究了表达所需的分子参数。 T22 的强抗 HIV 活性结果表明，T22 的抗 HIV 活性是通过与细胞或病毒的手性成分相互作用介导的，并且细胞毒性和膜之间存在正相关性。我们甚至发现T22与T细胞表面结合，并且结合活性与抗HIV活性之间存在正相关性。此外，还鉴定了T22肽上的结合位点。3.溶液相。 T22的合成建立了利用溶液相技术大规模合成T22的方法，为机械和临床前研究提供充足的材料。4.区域选择性二硫化物的开发成键方法开发了一种使用AgOTf-DMSO/HCl系统的区域选择性二硫键形成方法，以促进含双二硫键和色氨酸的肽（例如T22类似物）的明确合成。5.T22的构效关系利用通过上述区域选择性二硫键形成方法，合成了几种T22类似物，并为构效关系研究提供了依据确定T22的活性位点和细胞毒性位点。这些发现将导致具有新作用机制的新型抗艾滋病药物的开发。