Passarini Ilaria, Rossiter Sharon, Malkinson John, Zloh Mire
School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.
UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX, UK.
Pharmaceutics. 2018 Jun 21;10(3):72. doi: 10.3390/pharmaceutics10030072.
Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.
具有抗菌特性的阳离子肽在自然界中广泛存在，多年来人们一直在对其进行研究，试图设计出新型抗生素。然而，到目前为止，临床上使用的此类分子极少，有时是因为其结构复杂，但主要还是由于与肽相关的不良药代动力学特征。这项工作的目的是研究阳离子肽，以确定常见的结构特征，这些特征可能有助于设计具有改善的类药物性质和抗革兰氏阴性菌活性的小肽或肽模拟物。我们研究了两组具有已知抗菌活性的阳离子肽（抗菌肽）。第一组参考肽包含蛋白质数据库（PDB）中具有实验已知构象的分子，第二组由对革兰氏阴性菌有活性但没有显著结构信息的短肽组成。第一组肽的预测结构与实验观察到的结构非常吻合，这使得我们能够利用计算得出的构象来分析第二组肽的结构特征。将实验可得或预测的肽构象以“全对全”的方式进行聚类，然后对数量最多的聚类进行分析。结果证实，无论处于何种环境，这些肽都倾向于呈现两亲性构象。还观察到带正电荷的氨基酸残基常常紧邻芳香族残基。最后，评估了一种用于研究短阳离子肽在类似膜环境（如十二烷基磷酸胆碱（DPC）胶束）存在下行为的方案。本文给出的结果为设计具有潜在抗菌活性的新型短肽提供了一种有前景的方法。
