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Current Pharmaceutical Design

Author(s): Marco Cavaco, Javier Valle , Ruben da Silva, João D.G. Correia, Miguel A. R. B Castanho, David Andreu* and Vera Neves*

DOI: 10.2174/1381612826666200213094556

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DPepH3, an Improved Peptide Shuttle for Receptor-independent Transport Across the Blood-Brain Barrier

Page: [1495 - 1506] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: 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), the 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.

Methods: The goal of this work was the development of a more proteolytic-resistant peptide, while keeping the translocation properties. The serum stability, cytotoxicity, in vitro BBB translocation, and internalization mechanism of DPepH3 was assessed and compared to the native peptide.

Results: DPepH3 demonstrates a much longer t1/2 compared to PepH3. We also confirm that BBB translocation is receptor-independent, which fully validates the enantiomer strategy chosen. In fact, we demonstrate that internalization occurs trough macropinocytosis. In addition, the enantiomer demonstrates to be non-cytotoxic towards endothelial cells as PepH3.

Conclusion: DPepH3 shows excellent translocation and internalization properties, safety, and improved stability. Taken together, our results place DPepH3 at the forefront of the second generation of BBB shuttles.

Keywords: Adsorption-mediated transcytosis, blood-brain barrier, D-amino acids, macropinocytosis, PepH3, peptide shuttles, stability.

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