Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides
Autor(a) principal: | |
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Data de Publicação: | 2008 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/11155 https://doi.org/10.1021/ja711247n |
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 behavior 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) × 103), 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 gel-phase 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. |
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Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor PeptidesSifuvirtide, 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 behavior 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) × 103), 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 gel-phase 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.American Chemical Society2008-04-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/11155http://hdl.handle.net/10316/11155https://doi.org/10.1021/ja711247nengJournal of the American Chemical Society. 130:19 (2008) 6215-62230002-7863Franquelim, Henri G.Loura, Luís M. S.Santos, Nuno C.Castanho, Miguel A. R. B.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-05-25T02:28:39Zoai:estudogeral.uc.pt:10316/11155Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:24.632449Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
title |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
spellingShingle |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides Franquelim, Henri G. |
title_short |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
title_full |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
title_fullStr |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
title_full_unstemmed |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
title_sort |
Sifuvirtide Screens Rigid Membrane Surfaces. Establishment of a Correlation between Efficacy and Membrane Domain Selectivity among HIV Fusion Inhibitor Peptides |
author |
Franquelim, Henri G. |
author_facet |
Franquelim, Henri G. Loura, Luís M. S. Santos, Nuno C. Castanho, Miguel A. R. B. |
author_role |
author |
author2 |
Loura, Luís M. S. Santos, Nuno C. Castanho, Miguel A. R. B. |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Franquelim, Henri G. Loura, Luís M. S. Santos, Nuno C. Castanho, Miguel A. R. B. |
description |
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 behavior 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) × 103), 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 gel-phase 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. |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008-04-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/11155 http://hdl.handle.net/10316/11155 https://doi.org/10.1021/ja711247n |
url |
http://hdl.handle.net/10316/11155 https://doi.org/10.1021/ja711247n |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of the American Chemical Society. 130:19 (2008) 6215-6223 0002-7863 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
American Chemical Society |
publisher.none.fl_str_mv |
American Chemical Society |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799133751172661248 |