Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

Abstract

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.

This work was supported by Ministerio de Educación y Ciencia (BIO2005-07592-CO2-02 to D.A., BFU2005-01855 and CTQ2008-0080 to M.A.J., CTQ2007-62245 to C.C.), Fondo de Investigaciones Sanitarias (PI061125 and RD 06/0021/0006 to L.R., PI040885 to D.A.), by the regional governments of Aragón (research group E40), Catalunya (SGR2005-00494), and Madrid (S-BIO-0260/2006).