A novel LRP1-binding peptide L57 that crosses the blood brain barrier.

Biochem Biophys Rep

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.

Published: December 2017

The blood-brain barrier (BBB) is a major obstacle to drug delivery into the central nervous system (CNS), in particular for macromolecules such as peptides and proteins. However, certain macromolecules can reach the CNS a receptor-mediated transcytosis (RMT) pathway, and low-density lipoprotein receptor-related protein 1 (LRP1) is one of the promising receptors for RMT. An LRP1 ligand peptide, Angiopep-2, was reported to pass through the BBB and deliver covalently conjugated drugs into the CNS. While conjugation of LRP1 ligands with drugs would be an effective approach for drug delivery to the CNS, no other reliable LRP1 ligands have been reported to date. In this study, we aimed to identify novel LRP1 ligands to further investigate LRP1-mediated RMT. Using phage display technology, we obtained a novel peptide, L57 (TWPKHFDKHTFYSILKLGKH-OH), with an EC value of 45 nM for binding to cluster 4 (Ser3332-Asp3779) of LRP1. L57 was stable in mouse plasma for up to 20 min. brain perfusion assay in mice revealed the significantly high BBB permeability of L57. In conclusion, we discovered L57, the first artificial LRP1-binding peptide with BBB permeability. Our findings will contribute to the development of RMT-based drugs for the treatment of CNS diseases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645116PMC
http://dx.doi.org/10.1016/j.bbrep.2017.07.003DOI Listing

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