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

Solanas, Concepción; Torre, Beatriz G. de la; Fernández Reyes, María; Santiveri, Clara M.; Jiménez, M. Ángeles; Rivas, Luis; Jiménez, Ana I.; Andreu Martínez, David; Cativiela, Carlos

doi:http://dx.doi.org/10.1021/jm800886n

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

Citation

Solanas C, de la Torre BG, Fernández-Reyes M, Santiveri CM, Jiménez MA, Rivas L et al. Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn. J Med Chem. 2009;52(3):664-74. DOI: 10.1021/jm800886n

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.