Study on Design of Amphiphilic Functional Peptides and Their Action to Lipid Membranes

肽不仅有助于阐明作用机制和结构-功能关系，而且有助于药物设计和功能材料的建模。我们研究了抗菌肽pleurocidin （Ple）和bactenecin 5 （Bac 5）的结构-功能关系，化学修饰溶血凝集素CEL-III对其细胞毒活性的影响，以及利用阳离子两亲肽作为基因载体进入细胞。1)利用一些氨基酸取代的Ple类似物，研究了它们与脂质和细胞膜的相互作用。发现Ple的疏水性和正电荷的平衡对抗菌活性很重要。关于Bac 5，很明显，中心重复区域的一定链长度对抗菌活性至关重要，强阳离子n端部分增强了活性。2)通过Gly-OMe修饰CEL-III中Glu和Asp残基侧链，不仅溶血活性降低，而且糖结合和凝集活性也大大降低，表明结合位点或附近的羧基残基被修饰，与碳水化合物的结合将被中断。3)用半乳糖修饰阳离子两亲肽，并利用人肝癌细胞系评价其DNA转移能力。随着半乳糖残留量的增加，活性也随之提高。此外，我们发现dna -半乳糖修饰肽复合物的内化是由受体介导的内吞作用引起的。

Peptide contributes not only elucidation of action mechanism and structure-function relationship but also to drug design and modeling of functional materials. We have studied the structure-function relationship of antibacterial peptides, pleurocidin (Ple) and bactenecin 5 (Bac 5), effect of chemical modification of hemolytic lectin CEL-III on its cytotoxic activity, and use of cationic amphiphilic peptides as gene carriers into cells. 1) Using some amino acid-substituted Ple analogs, we examined their interaction with lipid and cell membranes. Balance of hydrophobicity and positive charge of Ple was found to be important for antibacterial activity. About Bac 5, it became clear that a certain chain length in the central repeating region is essential for antibacterial activity and the strongly cationic N-terminal portion enhances the activity. 2) By modification of the side chains of Glu and Asp residues in CEL-III with Gly-OMe, not only hemolytic activity but also carbohydrate-binding and agglutinative activities were greatly decreased, suggesting that carboxylic residues at the binding or near site are modified and the binding with carbohydrate would be interrupted. 3) Cationic amphiphilic peptides were modified with galactose, and their DNA transfer ability was evaluated using a human hepatoma cell line. Higher ability was observed with increasing galactose residues. Furthermore, we found that internalization of the DNA-galactose-modified peptide complexes is caused by the receptor-mediated endocytosis.