title: Novel Peptides Derived from Dengue Virus Capsid Protein Translocate Reversibly the Blood-Brain Barrier through a Receptor-Free Mechanism.
abstract: The delivery of therapeutic molecules to the central nervous system is hampered by poor delivery across the blood-brain barrier (BBB). Several strategies have been proposed to enhance transport into the brain, including invasive techniques and receptor-mediated transport (RMT). Both approaches have several drawbacks, such as BBB disruption, receptor saturation, and off-target effects, raising safety issues. Herein, we show that specific domains of Dengue virus type 2 capsid protein (DEN2C) can be used as trans-BBB peptide vectors. Their mechanism of translocation is receptor-independent and consistent with adsorptive-mediated transport (AMT). One peptide in particular, named PepH3, reaches equilibrium distribution concentrations across the BBB in less than 24 h in a cellular in vitro assay. Importantly, in vivo biodistribution data with radiolabeled peptide derivatives show high brain penetration. In addition, there is fast clearance from the brain and high levels of excretion, showing that PepH3 is a very good candidate to be used as a peptide shuttle taking cargo in and out of the brain.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Vera
authors.identifier: 0000-0002-2989-7208
authors.initials: V
authors.lastname: Neves
authors.affiliation: CIISA - Faculdade de Medicina Veterinária, Universidade de Lisboa , Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal.
authors.forename: Frederico
authors.initials: F
authors.lastname: Aires-da-Silva
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Campus Tecnológico e Nuclear, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Maurício
authors.initials: M
authors.lastname: Morais
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Campus Tecnológico e Nuclear, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Campus Tecnológico e Nuclear, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ribeiro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Antónia
authors.initials: A
authors.lastname: Pinto
authors.affiliation: CIISA - Faculdade de Medicina Veterinária, Universidade de Lisboa , Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Aguiar
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Gaspar
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Campus Tecnológico e Nuclear, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Campus Tecnológico e Nuclear, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: João D G
authors.initials: JDG
authors.lastname: Correia
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Miguel A R B
authors.identifier: 0000-0001-7891-7562
authors.initials: MARB
authors.lastname: Castanho
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003716:Dengue Virus / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007553:Isotope Labeling; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D036022:Capsid Proteins; D010455:Peptides