Therapeutic index of gramicidin S is strongly modulated by D-phenylalanine analogues at the beta-turn.
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.
Solanas
Concepción
C
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.
de la Torre
Beatriz G
BG
Fernández-Reyes
María
M
Santiveri
Clara M
CM
Jiménez
M Angeles
MA
Rivas
Luis
L
Jiménez
Ana I
AI
Andreu
David
D
Cativiela
Carlos
C
D040981:Acinetobacter baumannii / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D004912:Erythrocytes / Q000187:drug effects; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006461:Hemolysis / Q000187:drug effects; D053878:Hemolytic Agents / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D019906:Nuclear Magnetic Resonance, Biomolecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D017433:Protein Structure, Secondary; D012756:Sheep; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry
D053878:Hemolytic Agents; D044005:Tetrahydroisoquinolines; D006096:Gramicidin; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D010649:Phenylalanine