Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

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• dc.contributor.author Solanas, Concepción
• dc.contributor.author Torre, Beatriz G. de la
• dc.contributor.author Fernández Reyes, María
• dc.contributor.author Santiveri, Clara M.
• dc.contributor.author Jiménez, M. Ángeles
• dc.contributor.author Rivas, Luis
• dc.contributor.author Jiménez, Ana I.
• dc.contributor.author Andreu Martínez, David
• dc.contributor.author Cativiela, Carlos
• dc.date.accessioned 2019-02-25T08:52:07Z
• dc.date.available 2019-02-25T08:52:07Z
• dc.date.issued 2009
• dc.description.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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Solanas 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/jm800886n
• dc.identifier.doi http://dx.doi.org/10.1021/jm800886n
• dc.identifier.issn 0022-2623
• dc.identifier.uri http://hdl.handle.net/10230/36669
• dc.language.iso spa
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof Journal of Medicinal Chemistry. 2009;52(3):664-74
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/BIO2005-07592-CO2-02
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/BFU2005-01855
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/CTQ2008-0080
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/CTQ2007-62245
• dc.rights 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
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Gramidicin S
• dc.subject.keyword Gramidicin S
• dc.subject.keyword Cationic antimicrobial peptides
• dc.subject.keyword d-Phe analogues
• dc.subject.keyword NMR
• dc.subject.keyword β-sheet structure
• dc.title Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion