Therapeutic Index of Gramicidin S is Strongly Modulated by D-phenylalanine Analogues at the Beta-turn

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Jan 10

PMID 19132829

Citations 7

Authors

Concepcion Solanas

Beatriz G de la Torre

Maria Fernandez-Reyes

Clara M Santiveri

M Angeles Jimenez

Luis Rivas

Ana I Jimenez

David Andreu

Carlos Cativiela

Affiliations

Soon will be listed here.

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.

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