Strøm Morten B, Haug Bengt Erik, Rekdal Oystein, Skar Merete L, Stensen Wenche, Svendsen John S
Department of Chemistry, University of Tromsø, Norway.
Biochem Cell Biol. 2002;80(1):65-74. doi: 10.1139/o01-236.
This review focuses on important structural features affecting the antimicrobial activity of 15-residue derivatives of lactoferricins. Our investigations are based on an alanine-scan of a 15-residue bovine lactoferricin derivative that revealed the absolute necessity of two tryptophan residues for antimicrobial activity. This "tryptophan-effect" was further explored in homologous derivatives of human, caprine, and porcine lactoferricins by the incorporation of one additional tryptophan residue, and by increasing the content of tryptophan in the bovine derivative to five residues. Most of the resulting peptides display a substantial increase in antimicrobial activity. To identify which molecular properties make tryptophan so effective, a series of bovine lactoferricin derivatives were prepared containing non-encoded unnatural aromatic amino acids, which represented various aspects of the physicochemical nature of tryptophan. The results clearly demonstrate that tryptophan is not unique since most of the modified peptides were of higher antimicrobial potency than the native peptide. The size and three-dimensional shape of the inserted "super-tryptophans" are the most important determinants for the high antimicrobial activity of the modified peptides. This review also describes the use of a "soft-modeling" approach in order to identify important structural parameters affecting the antimicrobial activity of modified 15-residue murine lactoferricin derivatives. This QSAR-study revealed that the net charge, charge asymmetry, and micelle affinity of the peptides were the most important structural parameters affecting their antimicrobial activity.
本综述聚焦于影响乳铁蛋白15肽衍生物抗菌活性的重要结构特征。我们的研究基于对一种15肽牛乳铁蛋白衍生物的丙氨酸扫描，该扫描揭示了两个色氨酸残基对抗菌活性的绝对必要性。通过在人、山羊和猪乳铁蛋白的同源衍生物中额外引入一个色氨酸残基，并将牛衍生物中的色氨酸含量增加到五个残基，进一步探究了这种“色氨酸效应”。大多数所得肽的抗菌活性大幅提高。为了确定哪些分子特性使色氨酸如此有效，制备了一系列含有非编码非天然芳香族氨基酸的牛乳铁蛋白衍生物，这些氨基酸代表了色氨酸物理化学性质的各个方面。结果清楚地表明，色氨酸并非独一无二，因为大多数修饰后的肽比天然肽具有更高的抗菌效力。插入的“超级色氨酸”的大小和三维形状是修饰后肽具有高抗菌活性的最重要决定因素。本综述还描述了使用“软建模”方法来确定影响修饰后的15肽小鼠乳铁蛋白衍生物抗菌活性的重要结构参数。这项定量构效关系研究表明，肽的净电荷、电荷不对称性和胶束亲和力是影响其抗菌活性的最重要结构参数。
