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Structure-stability-function mechanistic links in the anti-measles virus action of tocopherol-derivatized peptide nanoparticles

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dc.contributor.authorFigueira, Tiago Nascimento
dc.contributor.authorMendonça, Diogo A.
dc.contributor.authorGaspar, Diana
dc.contributor.authorMelo, Manuel N.
dc.contributor.authorMoscona, Anne
dc.contributor.authorPorotto, Matteo
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorVeiga, Ana Salomé
dc.date.accessioned2019-03-26T12:01:27Z
dc.date.available2019-03-26T12:01:27Z
dc.date.issued2018
dc.description© 2018 American Chemical Societypt_PT
dc.description.abstractMeasles remains one of the leading causes of child mortality worldwide and is re-emerging in some countries due to poor vaccine coverage, concomitant with importation of measles virus (MV) from endemic areas. The lack of specific chemotherapy contributes to negative outcomes, especially in infants or immunodeficient individuals. Fusion inhibitor peptides derived from the MV Fusion protein C-terminal Heptad Repeat (HRC) targeting MV envelope fusion glycoproteins block infection at the stage of entry into host cells, thus preventing viral multiplication. To improve efficacy of such entry inhibitors, we have modified a HRC peptide inhibitor by introducing properties of self-assembly into nanoparticles (NP) and higher affinity for both viral and cell membranes. Modification of the peptide consisted of covalent grafting with tocopherol to increase amphipathicity and lipophilicity (HRC5). One additional peptide inhibitor consisting of a peptide dimer grafted to tocopherol was also used (HRC6). Spectroscopic, imaging, and simulation techniques were used to characterize the NP and explore the molecular basis for their antiviral efficacy. HRC5 forms micellar stable NP while HRC6 aggregates into amorphous, loose, unstable NP. Interpeptide cluster bridging governs NP assembly into dynamic metastable states. The results are consistent with the conclusion that the improved efficacy of HRC6 relative to HRC5 can be attributed to NP instability, which leads to more extensive partition to target membranes and binding to viral target proteins.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e a Tecnologia (FCT-MCTES) Project PTDC/QEQ-MED/4412/2014. T.N.F., D.A.M,. and D.G. acknowledge individual fellowships SFRH/BD/5283/2013, PD/BD/ 136752/2018 and SFRH/BPD/109010/2015 funded by FCT-MCTES. A.S.V. acknowledges funding under the Investigator Programme (IF/00803/2012) from FCTMCTES. M.N.M. acknowledges Grant LISBOA-01-0145- FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by Fundo Europeu de Desenvolvimento Regional (FEDER) and FCT-MCTES. A.M. acknowledges Grants RO1AI114736, R33AI101333, and RO1AI031971, and M.P. acknowledges grants R01AI119762, R01AI121349, and R01NS105699 funded by the National Institutes of Health (NIH).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationACS Nano 2018, 12, 10, 9855-9865pt_PT
dc.identifier.doi10.1021/acsnano.8b01422pt_PT
dc.identifier.issn1936-0851
dc.identifier.urihttp://hdl.handle.net/10451/37690
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relationSFRH/BD/5283/2013pt_PT
dc.relationTowards the development of innovative highly effective dual action anti-HIV peptides
dc.relationIF/00803/2012pt_PT
dc.relationCell-cell direct/indirect communication in metastatic breast cancer as a control point in oncotherapy
dc.relation.publisherversionhttps://pubs.acs.org/journal/ancac3pt_PT
dc.subjectSelf-assemblingpt_PT
dc.subjectPeptidept_PT
dc.subjectNanoparticlept_PT
dc.subjectMetastablept_PT
dc.subjectAntiviralpt_PT
dc.subjectFusion inhibitorpt_PT
dc.subjectMeasles viruspt_PT
dc.titleStructure-stability-function mechanistic links in the anti-measles virus action of tocopherol-derivatized peptide nanoparticlespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTowards the development of innovative highly effective dual action anti-HIV peptides
oaire.awardTitleCell-cell direct/indirect communication in metastatic breast cancer as a control point in oncotherapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQEQ-MED%2F4412%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F109010%2F2015/PT
oaire.citation.endPage9865pt_PT
oaire.citation.startPage9855pt_PT
oaire.citation.titleACS Nanopt_PT
oaire.citation.volume12pt_PT
oaire.fundingStream3599-PPCDT
person.familyNameFigueira
person.familyNameGaspar
person.familyNameCastanho
person.familyNameVeiga
person.givenNameTiago
person.givenNameDiana
person.givenNameMiguel
person.givenNameAna Salome
person.identifier103438
person.identifier.orcid0000-0002-0813-0745
person.identifier.orcid0000-0002-9602-567X
person.identifier.orcid0000-0001-7891-7562
person.identifier.orcid0000-0002-9892-2243
person.identifier.ridM-9562-2015
person.identifier.scopus-author-id55180303000
person.identifier.scopus-author-id56605575600
person.identifier.scopus-author-id56745037100
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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