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A novel LRP1-binding peptide L57 that crosses the blood ...
Skip to main content Skip to article View PDF Under a Creative Commons license Open access Highlights • The first artificial LRP1-binding peptide L57 was discovered by phage display. • L57 binds the extracellular domain of LRP1 with an EC 50 binding value of 2
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Under a Creative Commons license
Open access
Highlights
- •
The first artificial LRP1-binding peptide L57 was discovered by phage display.
- •
L57 binds the extracellular domain of LRP1 with an EC50 binding value of 24 nM.
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L57 exhibits brain uptake in in situ brain perfusion and i.v. injection in mice.
Abstract
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 via 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 EC50 value of 45 nM for binding to cluster 4 (Ser3332–Asp3779) of LRP1. L57 was stable in mouse plasma for up to 20 min. In situ 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.
Abbreviations
BBB
blood brain barrier
CNS
central nervous system
LRP1
low-density lipoprotein receptor-related protein 1
RMT
receptor-mediated transcytosis
Keywords
Blood brain barrier
Low-density lipoprotein receptor-related protein 1
Peptide
Phage display
Receptor-mediated transcytosis
1These authors contributed equally to this work.
© 2017 Published by Elsevier B.V.