Cirac Anna D, Torné Maria, Badosa Esther, Montesinos Emilio, Salvador Pedro, Feliu Lidia, Planas Marta
LIPPSO, Departament de Química, University of Girona, Maria Aurèlia Capmany 69, 17003 Girona, Spain.
Institut de Química Computacional i Catàlisi i Departament de Química, University of Girona, Maria Aurèlia Capmany 69, 17003 Girona, Spain.
Molecules. 2017 Jun 24;22(7):1054. doi: 10.3390/molecules22071054.
A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ) () and c(KLKKKFKKLQ) () is reported. First, the secondary β-structure of and was analyzed by carrying out molecular dynamics (MD) simulations. Then, based on the sequence pattern and the β-structure of or , fifteen analogues were designed and synthesized on solid-phase. The best peptides (, and ) showed minimum inhibitory concentration (MIC) values <6.2 μM against pv. and pv. , and an MIC value of 12.5 to 25 μM against , being as active as and . Interestingly, these three analogues followed the structural pattern defined from the MD simulations of the parent peptides. Thus, maintained the parallel alignment of the hydrophilic pairs K¹-K⁸, K²-K⁷, and K⁴-K⁵, whereas and included the two hydrophilic interactions K³-Q and K⁵-K⁸. In short, MD simulations have proved to be very useful for ascertaining the structural features of cyclic peptides that are crucial for their biological activity. Such approaches could be further employed for the development of new antibacterial cyclic peptides.
报道了一种从先导化合物c(KKLKKFKKLQ)()和c(KLKKKFKKLQ)()设计抗菌环肽的策略。首先，通过进行分子动力学(MD)模拟分析了和的二级β结构。然后，基于或的序列模式和β结构，在固相上设计并合成了15种类似物。最佳肽(、和)对pv.和pv.的最小抑菌浓度(MIC)值<6.2 μM，对的MIC值为12.5至25 μM，与和活性相当。有趣的是，这三种类似物遵循了母体肽MD模拟所定义的结构模式。因此，保持了亲水性对K¹-K⁸、K²-K⁷和K⁴-K⁵的平行排列，而和则包括两个亲水性相互作用K³-Q和K⁵-K⁸。简而言之，MD模拟已被证明对于确定对其生物活性至关重要的环肽的结构特征非常有用。此类方法可进一步用于开发新型抗菌环肽。
