Rational design of α-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index
Rational design of α-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index
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DOI：
10.1074/jbc.m413406200
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Hodges, RS
中科院分区：
文献类型：
--
作者：
Chen, YX;Mant, CT;Hodges, RS
在本研究中，26个残基的肽序列Ac-KWKSFLKTFKSAVKTVLHTALKAISS-amide（V-681）被用作框架，以研究肽的疏水性/亲水性、两亲性和螺旋性（由两亲性螺旋的极性和非极性面的中心的单个氨基酸取代诱导）对生物活性的影响。肽类似物还通过反相高效液相色谱中的温度分布进行了研究，从5到80摄氏度，以评估分子在溶液中的自缔合能力，这是了解肽抗微生物和溶血活性的另一个重要参数。较高的能力，在溶液中的自缔合与较弱的抗菌活性和较强的溶血活性的肽。生物学研究表明，强溶血活性的肽通常与高疏水性、高两亲性和高螺旋性相关。在大多数情况下，D-氨基酸取代的肽具有增强的平均抗菌活性相比，L-非对映异构体。V-681对革兰氏阴性菌和革兰氏阳性菌的治疗指数分别提高了90倍和23倍。通过简单地取代中心的疏水性或亲水性氨基酸残基的非极性或极性面的V-681的这些两亲性衍生物与一系列选定的D-/L-氨基酸，我们证明了这种方法具有良好的潜力，抗菌肽的合理设计与增强的活动。
In the present study, the 26-residue peptide sequence Ac-KWKSFLKTFKSAVKTVLHTALKAISS-amide (V-681) was utilized as the framework to study the effects of peptide hydrophobicity/hydrophilicity, amphipathicity, and helicity ( induced by single amino acid substitutions in the center of the polar and nonpolar faces of the amphipathic helix) on biological activities. The peptide analogs were also studied by temperature profiling in reversed-phase high performance liquid chromatography, from 5 to 80 degrees C, to evaluate the self-associating ability of the molecules in solution, another important parameter in understanding peptide antimicrobial and hemolytic activities. A higher ability to self-associate in solution was correlated with weaker antimicrobial activity and stronger hemolytic activity of the peptides. Biological studies showed that strong hemolytic activity of the peptides generally correlated with high hydrophobicity, high amphipathicity, and high helicity. In most cases, the D-amino acid substituted peptides possessed an enhanced average antimicrobial activity compared with L-diastereomers. The therapeutic index of V-681 was improved 90- and 23-fold against Gram-negative and Gram-positive bacteria, respectively. By simply replacing the central hydrophobic or hydrophilic amino acid residue on the nonpolar or the polar face of these amphipathic derivatives of V-681 with a series of selected D-/L-amino acids, we demonstrated that this method has excellent potential for the rational design of antimicrobial peptides with enhanced activities.