Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure

Detalhes bibliográficos
Autor(a) principal: Augusto, Marcelo T.
Data de Publicação: 2014
Outros Autores: Hollmann, Axel, Castanho, Miguel A. R. B., Porotto, Matteo, Pessi, Antonello, Santos, Nuno C.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/23254
Resumo: © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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spelling Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposureHIV-1Cholesterol-taggingDrug designBlood cells© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.Objectives: The aim of the present work was to evaluate the interaction of two new HIV fusion inhibitors {HIVP3 [C34–polyethylene glycol (PEG)4–cholesterol] and HIVP4 [(C34–PEG4)2–cholesterol]} with membrane model systems and human blood cells in order to clarify where and how the fusion inhibitors locate, allowing us to understand their mechanism of action at the molecular level, and which strategies may be followed to increase efficacy. Methods: Lipid vesicles with defined compositions were used for peptide partition and localization studies, based on the intrinsic fluorescence of HIVP3 and HIVP4. Lipid monolayers were employed in surface pressure studies. Finally, human erythrocytes and peripheral blood mononuclear cells (PBMCs) isolated from blood samples were used in dipole potential assays. Results: Membrane partition, dipole potential and surface pressure assays indicate that the new fusion inhibitors interact preferentially with cholesterol-rich liquid-ordered membranes, mimicking biological membrane microdomains known as lipid rafts. HIVP3 and HIVP4 are able to interact with human erythrocytes and PBMCs to a similar degree as a previously described simpler drug with monomeric C34 and lacking the PEG spacer, C34–cholesterol. However, the pocket-binding domain (PBD) of both HIVP3 and HIVP4 is more exposed to the aqueous environment than in C34–cholesterol. Conclusions: The present data allow us to conclude that more efficient blocking of HIV entry results from the synergism between the membranotropic behaviour and the enhanced exposure of the PBD.This work was partially supported by Fundação para a Ciência e a Tecnologia—Ministério do Ensino e da Ciência (FCT-MEC, Portugal) projects PTDC/QUI-BIQ/104787/2008 and DELIN-HIVERA/0002-2013, and by National Institutes of Health (NIH, USA) project #R21NS076385 (to M. P.). A. H. also acknowledges FCT-MEC fellowship SFRH/BPD/72037/2010Oxford University PressRepositório da Universidade de LisboaAugusto, Marcelo T.Hollmann, AxelCastanho, Miguel A. R. B.Porotto, MatteoPessi, AntonelloSantos, Nuno C.2016-04-05T16:01:16Z20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/23254engJ Antimicrob Chemother 2014; 69: 1286 –12970305-7453doi:10.1093/jac/dkt529info: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:RCAAP2023-11-08T16:11:13Zoai:repositorio.ul.pt:10451/23254Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:40:41.606442Repositório 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 Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
title Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
spellingShingle Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
Augusto, Marcelo T.
HIV-1
Cholesterol-tagging
Drug design
Blood cells
title_short Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
title_full Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
title_fullStr Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
title_full_unstemmed Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
title_sort Improvement of HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure
author Augusto, Marcelo T.
author_facet Augusto, Marcelo T.
Hollmann, Axel
Castanho, Miguel A. R. B.
Porotto, Matteo
Pessi, Antonello
Santos, Nuno C.
author_role author
author2 Hollmann, Axel
Castanho, Miguel A. R. B.
Porotto, Matteo
Pessi, Antonello
Santos, Nuno C.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Augusto, Marcelo T.
Hollmann, Axel
Castanho, Miguel A. R. B.
Porotto, Matteo
Pessi, Antonello
Santos, Nuno C.
dc.subject.por.fl_str_mv HIV-1
Cholesterol-tagging
Drug design
Blood cells
topic HIV-1
Cholesterol-tagging
Drug design
Blood cells
description © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
publishDate 2014
dc.date.none.fl_str_mv 2014
2014-01-01T00:00:00Z
2016-04-05T16:01:16Z
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/10451/23254
url http://hdl.handle.net/10451/23254
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv J Antimicrob Chemother 2014; 69: 1286 –1297
0305-7453
doi:10.1093/jac/dkt529
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.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
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
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