Solanas Concepción, de la Torre Beatriz G, Fernández-Reyes María, Santiveri Clara M, Jiménez M Angeles, Rivas Luis, Jiménez Ana I, Andreu David, Cativiela Carlos
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.
J Med Chem. 2009 Feb 12;52(3):664-74. doi: 10.1021/jm800886n.
Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-D-Phe-Pro)2, with d-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all D-Phe substitutions are shown by NMR to preserve the overall beta-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating D-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the D-Tic aromatic ring and the Orn delta-amino group may help explain the improved antibiotic profile of this analogue.
已合成了阳离子抗菌肽短杆菌肽S（GS）的类似物环（缬氨酸-鸟氨酸-亮氨酸-D-苯丙氨酸-脯氨酸）₂，其中D-苯丙氨酸残基被不同的（大多为受限流动性的）替代物取代，并将其用于针对几种病原菌的构效关系研究。虽然核磁共振（NMR）显示所有D-苯丙氨酸替代物都保留了整体β-折叠构象，但它们会引起细微的结构改变，从而导致生物活性发生显著变化。特别是，掺入D-Tic（1,2,3,4-四氢异喹啉-3-羧酸）的类似物的治疗指数有适度但显著的提高，这主要是由于溶血效应急剧下降。NMR数据显示D-Tic芳香环与鸟氨酸δ-氨基之间的距离缩短，这一事实可能有助于解释该类似物改善的抗生素特性。
