LAUSR

The use of peptides as drug carriers across the blood-brain barrier (BBB) has increased significantly during the last decades. PepH3, a seven residue sequence (AGILKRW) derived from the α-helical domain of the dengue virus type-2 capsid protein, translocates across the BBB with very low toxicity. Somehow predictably from its size and sequence, PepH3 is degraded in serum relatively fast. Among strategies to increase peptide half-life (t1/2), use of the enantiomer (wholly made of D-amino acid residues) can be quite successful if the peptide interacts with a target in non-stereospecific fashion. Here we report that aGilkrw (DPepH3), the enantiomer of PepH3, has a much longer t1/2. We also confirm that BBB translocation is receptor-independent, which fully validates the enantiomer strategy chosen. Moreover, the cell internalization step that initiates transcytosis follows a macropinocytosis pathway. Taken together, our results place DPepH3 at the forefront of a second generation of BBB shuttles with excellent translocation and internalization properties, safety, and improved stability.