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Penetrating the blood brain barrier with new peptide porphyrin conjugates having anti HIV activity

2021Journal article Restricted access
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dc.contributor.authorMendonça, Diogo A.
dc.contributor.authorBakker, Mariët
dc.contributor.authorCruz-Oliveira, Christine
dc.contributor.authorNeves, Vera
dc.contributor.authorAngeles Jiménez, Maria
dc.contributor.authorDefaus, Sira
dc.contributor.authorCavaco, Marco
dc.contributor.authorVeiga, Ana Salomé
dc.contributor.authorCadima Couto, Carla Iris
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorAndreu, David
dc.contributor.authorTodorovski, Toni
dc.date.accessioned2023-06-01T14:27:14Z
dc.date.available2023-06-01T14:27:14Z
dc.date.issued2021
dc.descriptionCopyright © 2021 American Chemical Societypt_PT
dc.description.abstractPassing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide–drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide–porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.pt_PT
dc.description.sponsorshipWork supported by the La Caixa Health Foundation (project HR17_00409, ID 100010434, agreement LCF/PR/HR17/52150011), by the European Union (H2020-FETOPEN-2018-2019-2020-01 grant no 828774), and by the Spanish Ministry of Science and Innovation (AEI/FEDER grant CTQ2017-84371-P). NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB. Additional funding from Fundação para a Ciência e Tecnologia (FCT-MCTES) is also acknowledged for DA Mendonça (PD/BD/136752/2018) and for C. Cruz-Oliveira and I. Cadima-Couto (PTDC/BIA-VIR/29495/2017).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBioconjugate Chem. 2021, 32, 6, 1067–1077pt_PT
dc.identifier.doi10.1021/acs.bioconjchem.1c00123pt_PT
dc.identifier.eissn1520-4812
dc.identifier.issn1043-1802
dc.identifier.urihttp://hdl.handle.net/10451/57791
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_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.relationTargeting brain-resident viruses across the blood-brain barrier using peptide drugs.
dc.relation.publisherversionhttps://pubs.acs.org/journal/bcchespt_PT
dc.titlePenetrating the blood brain barrier with new peptide porphyrin conjugates having anti HIV activitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitle''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals
oaire.awardTitleTargeting brain-resident viruses across the blood-brain barrier using peptide drugs.
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/828774/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F136752%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-VIR%2F29495%2F2017/PT
oaire.citation.endPage1077pt_PT
oaire.citation.issue32pt_PT
oaire.citation.startPage1067pt_PT
oaire.citation.titleBioconjugate Chemistrypt_PT
oaire.citation.volume6pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
person.familyNameMendonça
person.familyNameCruz-Oliveira
person.familyNameNeves
person.familyNameCavaco
person.familyNameVeiga
person.familyNamecadima couto
person.familyNameCastanho
person.givenNameDiogo
person.givenNameChristine
person.givenNameVera
person.givenNameMarco
person.givenNameAna Salome
person.givenNamecarla iris
person.givenNameMiguel
person.identifier2135921
person.identifier953259
person.identifier1069324
person.identifier.ciencia-id2F1E-8D99-DA70
person.identifier.ciencia-id731E-A4B5-A2EB
person.identifier.ciencia-id671C-1860-A160
person.identifier.ciencia-id1412-63B8-7494
person.identifier.orcid0000-0001-8003-4662
person.identifier.orcid0000-0003-4838-0703
person.identifier.orcid0000-0002-2989-7208
person.identifier.orcid0000-0002-0938-9038
person.identifier.orcid0000-0002-9892-2243
person.identifier.orcid0000-0001-7398-5857
person.identifier.orcid0000-0001-7891-7562
person.identifier.ridO-2176-2018
person.identifier.scopus-author-id26537945300
person.identifier.scopus-author-id56745037100
person.identifier.scopus-author-id56605575600
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
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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