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

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  • dc.contributor.author Mendonça, Diogo A.
  • dc.contributor.author Bakker, Mariët
  • dc.contributor.author Cruz-Oliveira, Christine
  • dc.contributor.author Neves, Vera
  • dc.contributor.author Jiménez, Maria Angeles
  • dc.contributor.author Defaus, Sira
  • dc.contributor.author Cavaco, Marco
  • dc.contributor.author Salomé Veiga, Ana
  • dc.contributor.author Cadima-Couto, Iris
  • dc.contributor.author Castanho, Miguel A.R.B.
  • dc.contributor.author Andreu Martínez, David
  • dc.contributor.author Todorovski, Toni
  • dc.date.accessioned 2022-01-25T07:29:47Z
  • dc.date.available 2022-01-25T07:29:47Z
  • dc.date.issued 2021
  • dc.description.abstract Passing 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.
  • dc.description.sponsorship Work 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).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Mendonça DA, Bakker M, Cruz-Oliveira C, Neves V, Jiménez MA, Defaus S, Cavaco M, Veiga AS, Cadima-Couto I, Castanho MARB, Andreu D, Todorovski T. Penetrating the blood-brain barrier with new peptide-porphyrin conjugates having anti-HIV activity. Bioconjug Chem. 2021;32(6):1067-77. DOI: 10.1021/acs.bioconjchem.1c00123
  • dc.identifier.doi http://dx.doi.org/10.1021/acs.bioconjchem.1c00123
  • dc.identifier.issn 1043-1802
  • dc.identifier.uri http://hdl.handle.net/10230/52305
  • dc.language.iso eng
  • dc.publisher American Chemical Society (ACS)
  • dc.relation.ispartof Bioconjug Chem. 2021;32(6):1067-77
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/828774
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CTQ2017-84371-P
  • dc.rights © 2021 American Chemical Society. This work is licensed under a Creative Commons Attribution 4.0 International License
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.title Penetrating the blood-brain barrier with new peptide-porphyrin conjugates having anti-HIV activity
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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