Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids
Autor(a) principal: | |
---|---|
Data de Publicação: | 2014 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/13962 |
Resumo: | The human immunodeficiency virus type 1 (HIV-1) is a highly pathogenic and evasive virus, for which no cure has yet been achieved. The majority of the antiretroviral drugs developed over the years against this infection target key enzymes in HIV life cycle, such as reverse transcriptase, integrase and protease. Fusion of viral and host cell membranes is a crucial step in virus infectivity;therefore,the development of viral entry inhibitors has great advantages over conventional drugs, since they prevent the release of the viral content into the host cell. Previous studies showed that the antiviral activity of HIV-1inhibitor peptides is increased bythe addition of cholesterol and polyethylene glycol (PEG). The aim of the present work isto characterizethe interaction of enfuvirtide derived molecules by conjugation with cholesterol,palmitic acid or α-tocopherol as lipid anchors and PEG as spacer, with biomembrane model systems and human blood cells.Fluorescence spectroscopymethodologies, including membrane partition and fluorescence quenching assays,demonstrated that conjugation with lipids increasesthe peptides ability to interact with membranes of different compositions. In addition, the depth of peptide insertion into the membrane was assessed using lipophilic probes, revealing that the conjugated peptides are located in a more shallow position than the unconjugated one. Moreover, dipole potential assays showed that conjugated peptides exhibit a higher affinity towards cholesterol-rich membranes, as well as human blood cells, than the unconjugated peptide.Altogether, the obtained results indicate that a proper balance between membrane affinity and peptide exposure is required in order to enhance antiviral activity. Therefore, the addition of lipid moieties to an established fusion inhibitor such as enfuvirtide can be a promising strategy against HIV-1. |
id |
RCAP_6a3021029c6ab2a69060d1fc62897801 |
---|---|
oai_identifier_str |
oai:run.unl.pt:10362/13962 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
|
spelling |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipidsVIH-1Fusion inhibitorEnfuvirtideMembrane anchoring lipidsThe human immunodeficiency virus type 1 (HIV-1) is a highly pathogenic and evasive virus, for which no cure has yet been achieved. The majority of the antiretroviral drugs developed over the years against this infection target key enzymes in HIV life cycle, such as reverse transcriptase, integrase and protease. Fusion of viral and host cell membranes is a crucial step in virus infectivity;therefore,the development of viral entry inhibitors has great advantages over conventional drugs, since they prevent the release of the viral content into the host cell. Previous studies showed that the antiviral activity of HIV-1inhibitor peptides is increased bythe addition of cholesterol and polyethylene glycol (PEG). The aim of the present work isto characterizethe interaction of enfuvirtide derived molecules by conjugation with cholesterol,palmitic acid or α-tocopherol as lipid anchors and PEG as spacer, with biomembrane model systems and human blood cells.Fluorescence spectroscopymethodologies, including membrane partition and fluorescence quenching assays,demonstrated that conjugation with lipids increasesthe peptides ability to interact with membranes of different compositions. In addition, the depth of peptide insertion into the membrane was assessed using lipophilic probes, revealing that the conjugated peptides are located in a more shallow position than the unconjugated one. Moreover, dipole potential assays showed that conjugated peptides exhibit a higher affinity towards cholesterol-rich membranes, as well as human blood cells, than the unconjugated peptide.Altogether, the obtained results indicate that a proper balance between membrane affinity and peptide exposure is required in order to enhance antiviral activity. Therefore, the addition of lipid moieties to an established fusion inhibitor such as enfuvirtide can be a promising strategy against HIV-1.Santos, NunoHollmann, AxelRUNGregório, Susana dos Reis2016-12-01T01:30:16Z2014-112014-122014-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/13962enginfo: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:RCAAP2023-07-10T15:32:13ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
title |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
spellingShingle |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids Gregório, Susana dos Reis VIH-1 Fusion inhibitor Enfuvirtide Membrane anchoring lipids |
title_short |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
title_full |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
title_fullStr |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
title_full_unstemmed |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
title_sort |
Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids |
author |
Gregório, Susana dos Reis |
author_facet |
Gregório, Susana dos Reis |
author_role |
author |
dc.contributor.none.fl_str_mv |
Santos, Nuno Hollmann, Axel RUN |
dc.contributor.author.fl_str_mv |
Gregório, Susana dos Reis |
dc.subject.por.fl_str_mv |
VIH-1 Fusion inhibitor Enfuvirtide Membrane anchoring lipids |
topic |
VIH-1 Fusion inhibitor Enfuvirtide Membrane anchoring lipids |
description |
The human immunodeficiency virus type 1 (HIV-1) is a highly pathogenic and evasive virus, for which no cure has yet been achieved. The majority of the antiretroviral drugs developed over the years against this infection target key enzymes in HIV life cycle, such as reverse transcriptase, integrase and protease. Fusion of viral and host cell membranes is a crucial step in virus infectivity;therefore,the development of viral entry inhibitors has great advantages over conventional drugs, since they prevent the release of the viral content into the host cell. Previous studies showed that the antiviral activity of HIV-1inhibitor peptides is increased bythe addition of cholesterol and polyethylene glycol (PEG). The aim of the present work isto characterizethe interaction of enfuvirtide derived molecules by conjugation with cholesterol,palmitic acid or α-tocopherol as lipid anchors and PEG as spacer, with biomembrane model systems and human blood cells.Fluorescence spectroscopymethodologies, including membrane partition and fluorescence quenching assays,demonstrated that conjugation with lipids increasesthe peptides ability to interact with membranes of different compositions. In addition, the depth of peptide insertion into the membrane was assessed using lipophilic probes, revealing that the conjugated peptides are located in a more shallow position than the unconjugated one. Moreover, dipole potential assays showed that conjugated peptides exhibit a higher affinity towards cholesterol-rich membranes, as well as human blood cells, than the unconjugated peptide.Altogether, the obtained results indicate that a proper balance between membrane affinity and peptide exposure is required in order to enhance antiviral activity. Therefore, the addition of lipid moieties to an established fusion inhibitor such as enfuvirtide can be a promising strategy against HIV-1. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-11 2014-12 2014-11-01T00:00:00Z 2016-12-01T01:30:16Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/13962 |
url |
http://hdl.handle.net/10362/13962 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
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 |
|
repository.mail.fl_str_mv |
|
_version_ |
1777302909388587008 |