A novel linear amphipathic β-sheet cationic antimicrobial peptide with enhanced selectivity for bacterial lipids
A novel linear amphipathic β-sheet cationic antimicrobial peptide with enhanced selectivity for bacterial lipids
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DOI：
10.1074/jbc.m102865200
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发表时间：
2001-07-27
影响因子：
4.8
通讯作者：
Kari, UP
中科院分区：
文献类型：
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作者：
Blazyk, J;Wiegand, R;Kari, UP
所有已知的自然发生的线性阳离子肽在与脂质结合时采用两亲性α -螺旋构象，作为诱导细胞渗漏的第一步。我们设计了一个18个残基的肽（KIGAKI）(3)-NH2，它不具有作为α -螺旋的两亲性，但可以形成高度两亲性的β -片。傅里叶变换红外光谱和圆二色光谱证实，（KIGAKI）(3)-NH2与脂质结合时确实形成了β -片结构。该肽的抑菌活性与（KIAGKIA）(3)-NH2的抑菌活性进行了比较，并优于GMASKA-GAIAGKIAKVALKAL-NH2 （PGLa）和（KLAGLAK）(3)NH2，这两种肽在与膜结合时均形成两亲性α -螺旋。（KIGAKI）(3)-NH2在由酸性脂质（磷脂酰甘油）和中性脂质（磷脂酰胆碱）混合物组成的脂质囊泡中诱导渗漏的效果比其他肽差得多。然而，当磷脂酰乙醇胺取代磷脂酰胆碱时，PGLa和α -螺旋模型肽的裂解能力降低，而（KIGAKI）(3)-NH2的裂解能力提高。利用含有单个色氨酸残基的类似物进行的荧光实验显示，（KIGAKI）(3)-NH2与α -螺旋肽在与脂质囊泡的相互作用方面存在显著差异。由于数据表明细菌和哺乳动物脂质之间的选择性增强，线性两亲性β -片肽如（KIGAKI）3-NH2作为潜在的抗菌药物值得进一步研究。
All known naturally occurring linear cationic peptides adopt an amphipathic alpha -helical conformation upon binding to lipids as an initial step in the induction of cell leakage. We designed an 18-residue peptide, (KIGAKI)(3)-NH2, that has no amphipathic character as an alpha -helix but can form a highly amphipathic beta -sheet. When bound to lipids, (KIGAKI)(3)-NH2 did indeed form a beta -sheet structure as evidenced by Fourier transform infrared and circular dichroism spectroscopy. The antimicrobial activity of this peptide was compared with that of (KIAGKIA)(3)-NH2, and it was better than that of GMASKA-GAIAGKIAKVALKAL-NH2 (PGLa) and (KLAGLAK)(3)NH2, all of which form amphipathic alpha -helices when bound to membranes. (KIGAKI)(3)-NH2 was much less effective at inducing leakage in lipid vesicles composed of mixtures of the acidic lipid, phosphatidylglycerol, and the neutral lipid, phosphatidylcholine, as compared with the other peptides. However, when phosphatidylethanolamine replaced phosphatidylcholine, the lytic potency of PGLa and the alpha -helical model peptides was reduced, whereas that of (KIGAKI)(3)-NH2 was improved. Fluorescence experiments using analogs containing a single tryptophan residue showed significant differences between (KIGAKI)(3)-NH2 and the alpha -helical peptides in their interactions with lipid vesicles. Because the data suggest enhanced selectivity between bacterial and mammalian lipids, linear amphipathic beta -sheet peptides such as (KIGAKI)3-NH2 warrant further investigation as potential antimicrobial agents.