Refining the eosinophil cationic protein antibacterial pharmacophore by rational structure minimization

Marc Torrent, David Pulido, Beatriz G. De La Torre, M. Flor García-Mayoral, M. Victòria Nogués, Marta Bruix, David Andreu, Ester Boix

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22 Citations (Scopus)


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. © 2011 American Chemical Society.
Original languageEnglish
Pages (from-to)5237-5244
JournalJournal of Medicinal Chemistry
Publication statusPublished - 28 Jul 2011


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