九州影院

Protein therapeutics cannot reach the brain in sufficient amounts because of their low permeability across the blood-brain barrier (BBB). Although previously reported brain shuttle peptides may enhance BBB transport of some therapeutics, efficient transport of protein cargoes remains a challenge.

Here we develop BrainBikes, a new family of bicyclic protease-resistant peptide shuttles capable of increasing transport of proteins, including antibody derivatives. Utilizing a trifunctional chemical linker, we generate several bicyclic analogs from a linear peptide targeting the transferrin receptor (TfR1). All analogs have increased metabolic resistance and one of them, BrainBike-4 (BB4), displays high affinity for cells with high levels of TfR1.

First, we show BB4 can enhance the transport of a model fluorescent protein by 4-fold. Subsequently, we conjugate BB4 site-specifically to a single chain variable antibody fragment (scFv) utilizing a chemoenzymatic approach. Conjugation of BB4 increases 5 times the transport of the scFv in a human cell-based model of the BBB. Our results prove the potential of bicyclic peptidomimetics as brain shuttles and open up new opportunities for the transport of biotherapeutics across the BBB.