2026-04-13T04:59:01Zhttps://recercat.cat/oai/request
oai:recercat.cat:10230/366692025-12-13T21:25:51Zcom_2072_6col_2072_452952
RECERCAT author Solanas, Concepción author Torre, Beatriz G. de la author Fernández Reyes, María author Santiveri, Clara M. author Jiménez, M. Ángeles author Rivas, Luis author Jiménez, Ana I. author Andreu Martínez, David author Cativiela, Carlos 2019-02-25T08:52:07Z2019-02-25T08:52:07Z2009 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.This work was supported by Ministerio de Educación y Ciencia (BIO2005-07592-CO2-02 to D.A., BFU2005-01855 and CTQ2008-0080 to M.A.J., CTQ2007-62245 to C.C.), Fondo de Investigaciones Sanitarias (PI061125 and RD 06/0021/0006 to L.R., PI040885 to D.A.), by the regional governments of Aragón (research group E40), Catalunya (SGR2005-00494), and Madrid (S-BIO-0260/2006). This 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/jm800886n info:eu-repo/semantics/openAccess Gramidicin S Gramidicin S Cationic antimicrobial peptides d-Phe analogues NMR β-sheet structure Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion