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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/7324

Título: Sifuvirtide screens rigid membrane surfaces. Establishment of a correlation between efficacy and membrane domain selectivity among HIV fusion inhibitor peptides
Autor: Franquelim, Henri G.
Loura, Luís M. S.
Santos, Nuno C.
Castanho, Miguel A. R. B.
Issue Date: 2008
Editora: American Chemical Society
Resumo: Sifuvirtide, a 36 amino acid negatively charged peptide, is a novel and promising HIV fusion inhibitor, presently in clinical trials. Because of the aromatic amino acid residues of the peptide, its behaviour in aqueous solution and the interaction with lipid-membrane model systems (large unilammelar vesicles) were studied by using mainly fluorescence spectroscopy techniques (both steady-state and time-resolved). No significant aggregation of the peptide was observed with aqueous solution. Various biological and nonbiological lipid-membrane compositions were analyzed, and atomic force microscopy was used to visualize phase separation in several of those mixtures. Results showed no significant interaction of the peptide, neither with zwitterionic fluid lipid membranes (liquid-disordered phase), nor with cholesterol-rich membranes (liquid-ordered phase). However, significant partitioning was observed with the positively charged lipid models (Kp = (2.2 ± 0.3) × 10_3), serving as a positive control. Fluorescence quenching using Förster resonance acrylamide and lipophilic probes was carried out to study the location of the peptide in the membrane models. In the gel-phase DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) membrane model, an adsorption of the peptide at the surface of these membranes was observed and confirmed by using Förster resonance energy-transfer experiments. These results indicate a targeting of the peptide to gelphase domains relatively to liquid-disordered or liquid-ordered phase domains. This larger affinity and selectivity toward the more rigid areas of the membranes, where most of the receptors are found, or to viral membrane, may help explain the improved clinical efficiency of sifuvirtide, by providing a local increased concentration of the peptide at the fusion site
Descrição: © 2008 American Chemical Society
Arbitragem científica: yes
URI: hhtp://dx.doi.org/10.1021/ja711247n
http://hdl.handle.net/10451/7324
ISSN: 0002-7863
Versão do Editor: The definitive version is available at http://pubs.acs.org/
Appears in Collections:IMM - Artigos em Revistas Internacionais

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