Chemical biology tools for probing transcytosis at the blood-brain barrier

Rhiannon Beard*, David C.A. Gaboriau, Antony D. Gee, Edward W. Tate

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood-brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an in vitro BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure-activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles.

Original languageEnglish
Pages (from-to)10772-10778
Number of pages7
JournalChemical Science
Volume10
Issue number46
DOIs
Publication statusPublished - 1 Jan 2019

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