Refining the Eosinophil Cationic Protein Antibacterial Pharmacophore by Rational Structure Minimization

详细信息    查看全文

• 作者：Marc Torrent ; David Pulido ; Beatriz G. de la Torre ; M. Flor Garci虂a-Mayoral ; M. Victo虁ria Nogue虂s ; Marta Bruix ; David Andreu ; Ester Boix
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5237-5244
• 全文大小：882K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

Sequence analysis of eosinophil cationic protein (ECP), a ribonuclease of broad antimicrobial activity, allowed identification of residues 1鈥?5 as the antimicrobial domain. We have further dissected ECP(1鈥?5) with a view to defining the minimal requirements for antimicrobial activity. Structure-based downsizing has focused on both 伪-helices of ECP(1鈥?5) and yielded analogues with substantial potency against Gram-negative and -positive strains. Analogues ECP(8鈥?6) and ECP(6鈥?7)-Ahx-(23鈥?6) (Ahx, 6-aminohexanoic acid) involve 36% and 40% size reduction relative to (1鈥?5), 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鈥?7)-Ahx-(23鈥?6), in particular, is shown by NMR to preserve the helical traits of the native 8鈥?6 (伪1) and 33鈥?6 (伪2) regions and can be proposed as the minimal structure capable of reproducing the activity of the entire protein.