Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn
| Autor: | Clara M. Santiveri, Carlos Cativiela, Beatriz G. de la Torre, David Andreu, Luis Rivas, María José Fernández-Reyes, M. Angeles Jiménez, Ana I. Jiménez, Concepción Solanas |
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| Přispěvatelé: | Ministerio de Educación y Ciencia (España), Gobierno de Aragón, Generalitat de Catalunya, Comunidad de Madrid, National Cancer Institute (US), National Institutes of Health (US), European Commission |
| Předmět: |
Acinetobacter baumannii
Staphylococcus aureus Erythrocytes Stereochemistry Phenylalanine β-sheet structure Peptide Gramicidin S Microbial Sensitivity Tests Gramidicin S Hemolysis Protein Structure Secondary Article chemistry.chemical_compound Structure-Activity Relationship Tetrahydroisoquinolines Drug Discovery Cationic antimicrobial peptides Peptide synthesis Structure–activity relationship Animals Nuclear Magnetic Resonance Biomolecular Antibacterial agent chemistry.chemical_classification Sheep Hemolytic Agents d-Phe analogues Gramicidin Listeria monocytogenes Cyclic peptide NMR chemistry Amino Acid Substitution Molecular Medicine |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname Digital.CSIC. Repositorio Institucional del CSIC |
| Popis: | 11 pags, 5 figs, 3 tabs, 1 sch. -- Supporting information is available at the Publisher's web 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 β-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-tetrahydroiso- quinoline-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 δ-amino group may help explain the improved antibiotic profile of this analogue. © 2009 American Chemical Society. 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 project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. C.S. and C.M.S. thank Ministerio de Educación y Ciencia and Consejo Superior de Investigaciones Científicas-European Social Fund for an FPU and I3P fellowship, respectively. |
| Databáze: | OpenAIRE |
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