Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, E-08193 Cerdanyola del Vallès, Spain.
J Med Chem. 2011 Jul 28;54(14):5237-44. doi: 10.1021/jm200701g. Epub 2011 Jul 1.
Sequence analysis of eosinophil cationic protein (ECP), a ribonuclease of broad antimicrobial activity, allowed identification of residues 1-45 as the antimicrobial domain. We have further dissected ECP(1-45) with a view to defining the minimal requirements for antimicrobial activity. Structure-based downsizing has focused on both α-helices of ECP(1-45) and yielded analogues with substantial potency against Gram-negative and -positive strains. Analogues ECP(8-36) and ECP(6-17)-Ahx-(23-36) (Ahx, 6-aminohexanoic acid) involve 36% and 40% size reduction relative to (1-45), respectively, and display a remarkably ECP-like antimicrobial profile. Both retain segments required for self-aggregation and lipolysaccharide binding, as well as the bacterial agglutination ability of parent ECP. Analogue (6-17)-Ahx-(23-36), in particular, is shown by NMR to preserve the helical traits of the native 8-16 (α1) and 33-36 (α2) regions and can be proposed as the minimal structure capable of reproducing the activity of the entire protein.
对具有广谱抗菌活性的核糖核酸酶——嗜酸性粒细胞阳离子蛋白（ECP）进行序列分析，确定其抗菌域为 1-45 位氨基酸残基。我们进一步对 ECP（1-45）进行了剖析，旨在确定其抗菌活性的最小要求。基于结构的缩小主要集中在 ECP（1-45）的两个α-螺旋上，并得到了对革兰氏阴性和阳性菌株具有显著活性的类似物。ECP（8-36）和 ECP（6-17）-Ahx-（23-36）（Ahx，6-氨基己酸）的相对分子质量分别比（1-45）减少了 36%和 40%，表现出与 ECP 非常相似的抗菌特性。两者均保留了自我聚集和脂多糖结合所需的片段，以及亲本 ECP 的细菌凝集能力。特别是类似物（6-17）-Ahx-（23-36）通过 NMR 显示保留了天然 8-16（α1）和 33-36（α2）区域的螺旋特征，可以提出该结构是能够重现整个蛋白活性的最小结构。
