Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S

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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 2019-02-21T08:35:03Z
• dc.date.available 2019-02-21T08:35:03Z
• dc.date.issued 2010
• dc.description.abstract A series of gramicidin S (GS) analogues have been synthesized where the Phe (i + 1) and Pro (i + 2) residues of the beta-turn have been swapped while the respective chiralities (D-, L-) at each position are preserved, and Phe is replaced by surrogates with aromatic side chains of diverse size, orientation, and flexibility. Although most analogues preserve the beta-sheet structure, as assessed by NMR, their antibiotic activities turn out to be highly dependent on the bulkiness and spatial arrangement of the aromatic side chain. Significant increases in microbicidal potency against both Gram-positive and Gram-negative pathogens are observed for several analogues, resulting in improved therapeutic profiles. Data indicate that seemingly minor replacements at the GS beta-turn can have significant impact on antibiotic activity, highlighting this region as a hot spot for modulating GS plasticity and activity.
• dc.description.sponsorship This work was supported by Ministerio de Ciencia e Innovación (BIO2008-04487-CO3-02 to D.A., CTQ2008-00080/BQU to M.A.J., CTQ2007-62245 to C.C.), Fondo de Investigaciones Sanitarias (PI061125 and RD06/0021/0006 to L.R.), by the regional governments of Aragón (research group E40), Catalonia (SGR2008-492), and Madrid (COMBACT S-BIO-0260/2006). C.S. and C.M.S. thank Ministerio de Educación y Ciencia and Consejo Superior de Investigaciones Científicas-European Social Fund for FPU and I3P fellowships, respectively. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
• 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. Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S. J Med Chem. 2010;53(10):4119-29. DOI: 10.1021/jm100143f
• dc.identifier.doi http://dx.doi.org/10.1021/jm100143f
• dc.identifier.issn 0022-2623
• dc.identifier.uri http://hdl.handle.net/10230/36639
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof Journal of Medicinal Chemistry. 2010; 53(10):4119-29
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BIO2008-04487-CO3-0
• 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/jm100143f.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Gramidicin S
• dc.subject.keyword Cationic antimicrobial peptides
• dc.subject.keyword Phenylalanine analogs
• dc.subject.keyword NMR
• dc.subject.keyword β-turn
• dc.subject.keyword β-sheet structure
• dc.title Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion