Solanas, ConcepciónTorre, Beatriz G. de laFernández Reyes, MaríaSantiveri, Clara M.Jiménez, M. ÁngelesRivas, LuisJiménez, Ana I.Andreu Martínez, DavidCativiela, Carlos2019-02-252019-02-252009Solanas 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/jm800886n0022-2623http://hdl.handle.net/10230/36669Analogues 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.application/pdfspaThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of medicinal chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm800886ninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/jm800886nGramidicin SGramidicin SCationic antimicrobial peptidesd-Phe analoguesNMRβ-sheet structureinfo:eu-repo/semantics/openAccess