Therapeutic Index of Gramicidin S is Strongly Modulated by D-Phenylalanine Analogues at the b-Turn.
作者
Solanas, Concepcion;de la Torre, Beatriz G.;Fernandez-Reyes, Maria;Santiveri, Clara M.;Jimenez, M. Angeles;Rivas, Luis;Jimenez, Ana I.;Andreu, David;Cativiela, Carlos;
[摘要]：Analogs 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 b-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biol. activity. In particular, the analog 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 arom. ring and the Orn d-amino group may help explain the improved antibiotic profile of this analog.
