Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells

Autores
Gomes, Bárbara; Sanna, Giusepinna; Madeddu, Silvia; Hollmann, Axel; Santos, Nuno C.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Such a limitation has led to the development of other fusion inhibitor peptides, such as C34, that present the same structural domain as enfuvirtide (heptad repeat sequence) but have different functional domains (pocket-binding domain in the case of C34 and lipid-binding domain in the case of enfuvirtide). Recently, the antiviral properties of 25-hydroxycholesterol were demonstrated, which boosted the interest in this oxysterol. The combination of two distinct antiviral molecules, C34 and 25-hydroxycholesterol, may help to suppress the emergence of resistant viruses. In this work, we characterized the interaction of the C34-25-hydroxycholesterol conjugate with biomembrane model systems and human blood cells. Lipid vesicles and monolayers with defined lipid compositions were used as biomembrane model systems. The conjugate interacts preferentially with membranes rich in sphingomyelin (a lipid enriched in lipid rafts) and presents a poor partition to membranes composed solely of phosphatidylcholine and cholesterol. We hypothesize that cholesterol causes a repulsive effect that is overcome in the presence of sphingomyelin. Importantly, the peptide shows a preference for human peripheral blood mononuclear cells relative to erythrocytes, which shows its potential to target CD4 + cells. Antiviral activity results against different wild-type and drug-resistant HIV strains further demonstrated the potential of C34-HC as a good candidate for future studies.
Fil: Gomes, Bárbara. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; Portugal
Fil: Sanna, Giusepinna. University of Cagliary; Italia
Fil: Madeddu, Silvia. University of Cagliary; Italia
Fil: Hollmann, Axel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Santos, Nuno C.. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; Portugal
Materia
25-HYDROXYCHOLESTEROL
C34
FUSION
HUMAN IMMUNODEFICIENCY VIRUS
PEPTIDE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/147263
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/147263
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cellsGomes, BárbaraSanna, GiusepinnaMadeddu, SilviaHollmann, AxelSantos, Nuno C.25-HYDROXYCHOLESTEROLC34FUSIONHUMAN IMMUNODEFICIENCY VIRUSPEPTIDEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Such a limitation has led to the development of other fusion inhibitor peptides, such as C34, that present the same structural domain as enfuvirtide (heptad repeat sequence) but have different functional domains (pocket-binding domain in the case of C34 and lipid-binding domain in the case of enfuvirtide). Recently, the antiviral properties of 25-hydroxycholesterol were demonstrated, which boosted the interest in this oxysterol. The combination of two distinct antiviral molecules, C34 and 25-hydroxycholesterol, may help to suppress the emergence of resistant viruses. In this work, we characterized the interaction of the C34-25-hydroxycholesterol conjugate with biomembrane model systems and human blood cells. Lipid vesicles and monolayers with defined lipid compositions were used as biomembrane model systems. The conjugate interacts preferentially with membranes rich in sphingomyelin (a lipid enriched in lipid rafts) and presents a poor partition to membranes composed solely of phosphatidylcholine and cholesterol. We hypothesize that cholesterol causes a repulsive effect that is overcome in the presence of sphingomyelin. Importantly, the peptide shows a preference for human peripheral blood mononuclear cells relative to erythrocytes, which shows its potential to target CD4 + cells. Antiviral activity results against different wild-type and drug-resistant HIV strains further demonstrated the potential of C34-HC as a good candidate for future studies.Fil: Gomes, Bárbara. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; PortugalFil: Sanna, Giusepinna. University of Cagliary; ItaliaFil: Madeddu, Silvia. University of Cagliary; ItaliaFil: Hollmann, Axel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Santos, Nuno C.. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; PortugalAmerican Chemical Society2019-02-28info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/147263Gomes, Bárbara; Sanna, Giusepinna; Madeddu, Silvia; Hollmann, Axel; Santos, Nuno C.; Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells; American Chemical Society; Infectious Diseases; 5; 4; 28-2-2019; 582-5912373-8227CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00321info:eu-repo/semantics/altIdentifier/doi/10.1021/acsinfecdis.8b00321info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:26:37Zoai:ri.conicet.gov.ar:11336/147263instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:26:38.308CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
title Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
spellingShingle Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
Gomes, Bárbara
25-HYDROXYCHOLESTEROL
C34
FUSION
HUMAN IMMUNODEFICIENCY VIRUS
PEPTIDE
title_short Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
title_full Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
title_fullStr Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
title_full_unstemmed Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
title_sort Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells
dc.creator.none.fl_str_mv Gomes, Bárbara
Sanna, Giusepinna
Madeddu, Silvia
Hollmann, Axel
Santos, Nuno C.
author Gomes, Bárbara
author_facet Gomes, Bárbara
Sanna, Giusepinna
Madeddu, Silvia
Hollmann, Axel
Santos, Nuno C.
author_role author
author2 Sanna, Giusepinna
Madeddu, Silvia
Hollmann, Axel
Santos, Nuno C.
author2_role author
author
author
author
dc.subject.none.fl_str_mv 25-HYDROXYCHOLESTEROL
C34
FUSION
HUMAN IMMUNODEFICIENCY VIRUS
PEPTIDE
topic 25-HYDROXYCHOLESTEROL
C34
FUSION
HUMAN IMMUNODEFICIENCY VIRUS
PEPTIDE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Such a limitation has led to the development of other fusion inhibitor peptides, such as C34, that present the same structural domain as enfuvirtide (heptad repeat sequence) but have different functional domains (pocket-binding domain in the case of C34 and lipid-binding domain in the case of enfuvirtide). Recently, the antiviral properties of 25-hydroxycholesterol were demonstrated, which boosted the interest in this oxysterol. The combination of two distinct antiviral molecules, C34 and 25-hydroxycholesterol, may help to suppress the emergence of resistant viruses. In this work, we characterized the interaction of the C34-25-hydroxycholesterol conjugate with biomembrane model systems and human blood cells. Lipid vesicles and monolayers with defined lipid compositions were used as biomembrane model systems. The conjugate interacts preferentially with membranes rich in sphingomyelin (a lipid enriched in lipid rafts) and presents a poor partition to membranes composed solely of phosphatidylcholine and cholesterol. We hypothesize that cholesterol causes a repulsive effect that is overcome in the presence of sphingomyelin. Importantly, the peptide shows a preference for human peripheral blood mononuclear cells relative to erythrocytes, which shows its potential to target CD4 + cells. Antiviral activity results against different wild-type and drug-resistant HIV strains further demonstrated the potential of C34-HC as a good candidate for future studies.
Fil: Gomes, Bárbara. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; Portugal
Fil: Sanna, Giusepinna. University of Cagliary; Italia
Fil: Madeddu, Silvia. University of Cagliary; Italia
Fil: Hollmann, Axel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; Argentina. Universidad Nacional de Quilmes; Argentina
Fil: Santos, Nuno C.. Universidade Nova de Lisboa. Faculdade de Ciencias Medicas; Portugal
description The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Such a limitation has led to the development of other fusion inhibitor peptides, such as C34, that present the same structural domain as enfuvirtide (heptad repeat sequence) but have different functional domains (pocket-binding domain in the case of C34 and lipid-binding domain in the case of enfuvirtide). Recently, the antiviral properties of 25-hydroxycholesterol were demonstrated, which boosted the interest in this oxysterol. The combination of two distinct antiviral molecules, C34 and 25-hydroxycholesterol, may help to suppress the emergence of resistant viruses. In this work, we characterized the interaction of the C34-25-hydroxycholesterol conjugate with biomembrane model systems and human blood cells. Lipid vesicles and monolayers with defined lipid compositions were used as biomembrane model systems. The conjugate interacts preferentially with membranes rich in sphingomyelin (a lipid enriched in lipid rafts) and presents a poor partition to membranes composed solely of phosphatidylcholine and cholesterol. We hypothesize that cholesterol causes a repulsive effect that is overcome in the presence of sphingomyelin. Importantly, the peptide shows a preference for human peripheral blood mononuclear cells relative to erythrocytes, which shows its potential to target CD4 + cells. Antiviral activity results against different wild-type and drug-resistant HIV strains further demonstrated the potential of C34-HC as a good candidate for future studies.
publishDate 2019
dc.date.none.fl_str_mv 2019-02-28
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/147263
Gomes, Bárbara; Sanna, Giusepinna; Madeddu, Silvia; Hollmann, Axel; Santos, Nuno C.; Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells; American Chemical Society; Infectious Diseases; 5; 4; 28-2-2019; 582-591
2373-8227
CONICET Digital
CONICET
url http://hdl.handle.net/11336/147263
identifier_str_mv Gomes, Bárbara; Sanna, Giusepinna; Madeddu, Silvia; Hollmann, Axel; Santos, Nuno C.; Combining 25-hydroxycholesterol with an HIV fusion inhibitor peptide: Interaction with biomembrane model systems and human blood cells; American Chemical Society; Infectious Diseases; 5; 4; 28-2-2019; 582-591
2373-8227
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00321
info:eu-repo/semantics/altIdentifier/doi/10.1021/acsinfecdis.8b00321
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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