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Design and characterization of a novel dimeric blood–brain barrier penetrating TNFα inhibitor

dc.contributor.authorManrique-Suárez V
dc.contributor.authorMacaya L
dc.contributor.authorContreras M.A
dc.contributor.authorParra N
dc.contributor.authorMaura R
dc.contributor.authorGonzález A
dc.contributor.authorToledo J.R
dc.contributor.authorSánchez O.
dc.date.accessioned2022-09-14T14:33:36Z
dc.date.available2022-09-14T14:33:36Z
dc.date.created2021
dc.identifier.issn8873585
dc.identifier.urihttp://hdl.handle.net/11407/7423
dc.descriptionTumor necrosis factor-alpha (TNFα) inhibitors could prevent neurological disorders systemically, but their design generally relies on molecules unable to cross the blood–brain barrier (BBB). This research was aimed to design and characterize a novel TNFα inhibitor based on the angiopeptide-2 as a BBB shuttle molecule fused to the extracellular domain of human TNFα receptor 2 and a mutated vascular endothelial growth factor (VEGF) dimerization domain. This new chimeric protein (MTV) would be able to trigger receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP-1) and inhibit the cytotoxic effect of TNFα more efficiently because of its dimeric structure. Stably transformed CHO cells successfully expressed MTV, and its purification by Immobilized-Metal Affinity Chromatography (IMAC) rendered high purity degree. Mutated VEGF domain included in MTV did not show cell proliferation or angiogenic activities measured by scratch and aortic ring assays, which corroborate that the function of this domain is restricted to dimerization. The pairs MTV-TNFα (Kd 279 ± 40.9 nM) and MTV-LRP1 (Kd 399 ± 50.5 nM) showed high affinity by microscale thermophoresis, and a significant increase in cell survival was observed after blocking TNFα with MTV in a cell cytotoxicity assay. Also, the antibody staining in CHOK1 and bEnd3 cells demonstrated the adhesion of MTV to the LRP1 receptor located in the cell membrane. These results provide compelling evidence for the proper functioning of the three main domains of MTV individually, which encourage us to continue the research with this new molecule as a potential candidate for the systemic treatment of neurological disorders. © 2021 Wiley Periodicals LLC.eng
dc.language.isoeng
dc.publisherJohn Wiley and Sons Inc
dc.relation.isversionofhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85110537947&doi=10.1002%2fprot.26173&partnerID=40&md5=3f574b27f0643066ae2dd66a1f8d6bb7
dc.sourceProteins: Structure, Function and Bioinformatics
dc.titleDesign and characterization of a novel dimeric blood–brain barrier penetrating TNFα inhibitor
dc.typeArticle
dc.rights.accessrightsinfo:eu-repo/semantics/restrictedAccess
dc.publisher.programCiencias Básicas
dc.type.spaArtículo
dc.identifier.doi10.1002/prot.26173
dc.subject.keywordBlood–brain barriereng
dc.subject.keywordChimeric proteineng
dc.subject.keywordNeurological disordereng
dc.subject.keywordTNFαeng
dc.relation.citationvolume89
dc.relation.citationissue11
dc.relation.citationstartpage1508
dc.relation.citationendpage1521
dc.publisher.facultyFacultad de Ciencias Básicas
dc.affiliationManrique-Suárez, V., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
dc.affiliationMacaya, L., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
dc.affiliationContreras, M.A., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
dc.affiliationParra, N., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
dc.affiliationMaura, R., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
dc.affiliationGonzález, A., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile, Faculty of Basic Sciences, University of Medellin, Medellin, Colombia
dc.affiliationToledo, J.R., Biotechnology and Biopharmaceutical Laboratory, Pathophysiology Department, School of Biological Science, Universidad de Concepción, Concepcion, Chile, Center of Biotechnology and Biomedicine Spa, Concepción, Chile
dc.affiliationSánchez, O., Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile, Center of Biotechnology and Biomedicine Spa, Concepción, Chile
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