gramicidin-a and 1-2-3-4-tetrahydroisoquinoline-carboxylic-acid

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.

Topics: Acinetobacter baumannii; Amino Acid Substitution; Animals; Erythrocytes; Gramicidin; Hemolysis; Hemolytic Agents; Listeria monocytogenes; Microbial Sensitivity Tests; Nuclear Magnetic Resonance, Biomolecular; Phenylalanine; Protein Structure, Secondary; Sheep; Staphylococcus aureus; Structure-Activity Relationship; Tetrahydroisoquinolines