Branched BBB-shuttle peptides: chemoselective modification of proteins to enhance blood-brain barrier transport

The blood-brain barrier (BBB) hampers the delivery of therapeutic proteins into the brain. BBB-shuttle peptides have been conjugated to therapeutic payloads to increase the permeability of these molecules. However, most BBB-shuttles have several limitations, such as a lack of resistance to proteases...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2018-11, Vol.9 (44), p.8409-8415
Main Authors: Díaz-Perlas, Cristina, Oller-Salvia, Benjamí, Sánchez-Navarro, Macarena, Teixidó, Meritxell, Giralt, Ernest
Format: Article
Language:English
Subjects:
Biomolecules
Brain
Chemical compounds
Fluorescence
Organic chemistry
Payloads
Peptides
Permeability
Proteins
Quantum dots
Transport
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Summary:The blood-brain barrier (BBB) hampers the delivery of therapeutic proteins into the brain. BBB-shuttle peptides have been conjugated to therapeutic payloads to increase the permeability of these molecules. However, most BBB-shuttles have several limitations, such as a lack of resistance to proteases and low effectiveness in transporting large biomolecules. We have previously reported on the THRre peptide as a protease-resistant BBB-shuttle that is able to increase the transport of fluorophores and quantum dots . In this work, we have evaluated the capacity of linear and branched THRre to increase the permeability of proteins in cellular models of the BBB. With this purpose, we have covalently attached peptides with one or two copies of the BBB-shuttle to proteins in order to develop chemically well-defined peptide-protein conjugates. While THRre does not enhance the uptake and transport of a model protein in BBB cellular models, branched THRre peptides displaying two copies of the BBB-shuttle result in a 2.6-fold increase.
ISSN:2041-6520
2041-6539
DOI:10.1039/c8sc02415d