Branched BBB-shuttle peptides: chemoselectivemodification of proteins to enhance blood–brainbarrier transport

摘要

The blood–brain barrier (BBB) hampers the delivery of therapeutic proteins into the brain. BBB-shuttlepeptides 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 loweffectiveness in transporting large biomolecules. We have previously reported on the THRre peptide asa protease-resistant BBB-shuttle that is able to increase the transport of fluorophores and quantum dotsin vivo. In this work, we have evaluated the capacity of linear and branched THRre to increase thepermeability of proteins in cellular models of the BBB. With this purpose, we have covalently attachedpeptides with one or two copies of the BBB-shuttle to proteins in order to develop chemically welldefined peptide–protein conjugates. While THRre does not enhance the uptake and transport ofa model protein in BBB cellular models, branched THRre peptides displaying two copies of the BBBshuttle result in a 2.6-fold increase.