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

点击翻译按钮获取中文摘要

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