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DPepH3, an improved peptide shuttle for receptor-independent transport across the blood-brain barrier

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dc.contributor.authorCavaco, Marco
dc.contributor.authorValle, Javier
dc.contributor.authorSilva, Rúben
dc.contributor.authorCorreia, João D. G.
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorAndreu, David
dc.contributor.authorNeves, Vera
dc.date.accessioned2023-04-21T13:40:49Z
dc.date.available2023-04-21T13:40:49Z
dc.date.issued2020
dc.description© 2020 Bentham Science Publisherspt_PT
dc.description.abstractBackground: The use of peptides as drug carriers across the blood-brain barrier (BBB) has increased significantly during the last decades. PepH3, a seven residue sequence (AGILKRW) derived from the α-helical domain of the dengue virus type-2 capsid protein, translocates across the BBB with very low toxicity. Somehow predictably from its size and sequence, PepH3 is degraded in serum relatively fast. Among strategies to increase peptide half-life (t1/2), the use of the enantiomer (wholly made of D-amino acid residues) can be quite successful if the peptide interacts with a target in non-stereospecific fashion. Methods: The goal of this work was the development of a more proteolytic-resistant peptide, while keeping the translocation properties. The serum stability, cytotoxicity, in vitro BBB translocation, and internalization mechanism of DPepH3 was assessed and compared to the native peptide. Results: DPepH3 demonstrates a much longer t1/2 compared to PepH3. We also confirm that BBB translocation is receptor-independent, which fully validates the enantiomer strategy chosen. In fact, we demonstrate that internalization occurs trough macropinocytosis. In addition, the enantiomer demonstrates to be non-cytotoxic towards endothelial cells as PepH3. Conclusion: DPepH3 shows excellent translocation and internalization properties, safety, and improved stability. Taken together, our results place DPepH3 at the forefront of the second generation of BBB shuttles.pt_PT
dc.description.sponsorshipThe authors thank the Portuguese Fundação para a Ciência e a Tecnologia (FCT, grants PD/BD/128281/2017, PTDC/BBBNAN/1578/2014, UID/Multi/04349/2019 and PTDC/QUINUC/30147/2017), the Spanish Ministry of Economy and Innovation (MINECO, grants AGL2014-52395-C2-2-R, AGL2017-84097-C2-2-R and Maria de Maeztu Program for Centers of Excellence), Spain; the European Union H2020-MSCA-RISE-2014 program (grant no. 828774), and the “La Caixa” Banking Foundation (grant HR17-00409) for financial support.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCurrent Pharmaceutical Design, 2020, 26, 1495-1506pt_PT
dc.identifier.doi10.2174/1381612826666200213094556pt_PT
dc.identifier.eissn1873-4286
dc.identifier.issn1381-6128
dc.identifier.urihttp://hdl.handle.net/10451/57223
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBentham Science Publisherspt_PT
dc.relationPTDC/BBBNAN/1578/2014pt_PT
dc.relationTrans-BBB peptides for targeting brain metastasis
dc.relationPTDC/QUINUC/30147/2017pt_PT
dc.relation''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals
dc.relation.publisherversionhttps://www.eurekaselect.com/journal/29pt_PT
dc.subjectAdsorption-mediated transcytosispt_PT
dc.subjectBlood-brain barrierpt_PT
dc.subjectD-amino acidspt_PT
dc.subjectMacropinocytosispt_PT
dc.subjectPepH3pt_PT
dc.subjectPeptide shuttlespt_PT
dc.subjectStabilitypt_PT
dc.titleDPepH3, an improved peptide shuttle for receptor-independent transport across the blood-brain barrierpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTrans-BBB peptides for targeting brain metastasis
oaire.awardTitle''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128281%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/828774/EU
oaire.citation.endPage1506pt_PT
oaire.citation.issue13pt_PT
oaire.citation.startPage1495pt_PT
oaire.citation.titleCurrent Pharmaceutical Designpt_PT
oaire.citation.volume26pt_PT
oaire.fundingStreamH2020
person.familyNameCavaco
person.familyNameSilva
person.familyNameCorreia
person.familyNameCastanho
person.familyNameNeves
person.givenNameMarco
person.givenNameRúben
person.givenNameJoão
person.givenNameMiguel
person.givenNameVera
person.identifier1069324
person.identifier1064683
person.identifier953259
person.identifier.ciencia-id1412-63B8-7494
person.identifier.ciencia-id561A-878D-536F
person.identifier.ciencia-idEC11-F3E9-78A2
person.identifier.ciencia-id671C-1860-A160
person.identifier.orcid0000-0002-0938-9038
person.identifier.orcid0000-0003-3665-9571
person.identifier.orcid0000-0002-7847-4906
person.identifier.orcid0000-0001-7891-7562
person.identifier.orcid0000-0002-2989-7208
person.identifier.ridJ-7036-2013
person.identifier.ridO-2176-2018
person.identifier.scopus-author-id7202364104
person.identifier.scopus-author-id56605575600
person.identifier.scopus-author-id26537945300
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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