Effects of Aib residues insertion on the structural-functional properties of the frog skin-derived peptide esculentin-1a(1-21)NH2
Effects of Aib residues insertion on the structural-functional properties of the frog skin-derived peptide esculentin-1a(1-21)NH2
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DOI：
10.1007/s00726-016-2341-x
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发表时间：
2017-01-01
期刊：
影响因子：
3.5
通讯作者：
Mangoni, Maria Luisa
中科院分区：
文献类型：
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作者：
Biondi, Barbara;Casciaro, Bruno;Mangoni, Maria Luisa
抗菌肽（Antimicrobial peptides, AMPs）在生物体抵御微生物病原体的防御机制中发挥着关键作用，具有杀菌和免疫调节的双重特性。它们被认为是传统抗生素的一种有希望的替代品，因为细菌对传统抗生素的耐药性越来越强。近年来，蛙皮AMP esculentin-1a衍生物esculentin-1a(1-21)NH2 [Esc(1-21)]对革兰氏阴性菌具有较强且快速的溶膜活性，但对革兰氏阳性菌的溶膜活性较低。在这里，为了提高Esc（1-21）的α -螺旋度和对革兰氏阳性细菌的预期效力，我们设计了一个类似物，在其初级结构的1,10和18位上含有三个α -氨基异丁酸（Aib）残基。我们证明了Aib残基的加入：(1)通过圆二色性和二维核磁共振波谱证实，促进了Esc（1-21）的α -螺旋构象；(2)足以使该类似物比亲本肽对几种革兰氏阳性菌株更有活性，而不影响其对革兰氏阴性细菌的活性；(3)在抗菌活性浓度下对上皮细胞无毒性作用。这些结果表明，用Aib残基取代l -氨基酸对膜活性肽Esc（1-21）的结构和性质有有益的影响，使其成为设计和开发抗革兰氏阳性菌选择性药物的更好候选物。
Antimicrobial peptides (AMPs) play a key role in the defence mechanism of living organisms against microbial pathogens, displaying both bactericidal and immunomodulatory properties. They are considered as a promising alternative to the conventional antibiotics towards which bacteria are becoming highly resistant. Recently, a derivative of the frog skin AMP esculentin-1a, esculentin-1a(1-21)NH2 [Esc(1-21)], showed a strong and fast membranolytic activity against Gram-negative bacteria but with a lower efficacy against Gram-positive ones. Here, with the aim to increase the alpha-helicity of Esc(1-21) and the expected potency against Gram-positive bacteria, we designed an analog bearing three alpha-aminoisobutyric acid (Aib) residues at positions 1, 10, and 18 of its primary structure. We demonstrated that the incorporation of Aib residues: (1) promoted the alpha-helix conformation of Esc(1-21), as confirmed by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopies; (2) was sufficient to make this analog more active than the parent peptide against several Gram-positive bacterial strains without affecting its activity against Gram-negative bacteria; and (3) resulted to be devoid of toxic effect toward epithelial cells at the active antimicrobial concentrations. These results suggest that replacement of L-amino acids with Aib residues has beneficial effects on the structure and properties of the membrane-active peptide Esc(1-21), making it a better candidate for the design and development of selective drugs against Gram-positive bacteria.