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A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.

Abstract：

:The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drugs or drug-delivery vehicles. Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (KD as low as 216 pM), co-crystallized it with the receptor, and confirmed murine cross-reactivity. It accumulates in the mouse CNS at ~25% of blood levels (CNS blood content is only ~1%-6%) and delivers neurotensin, an otherwise non-BBB-penetrant neuropeptide, at levels capable of modulating CREB signaling in the mouse brain. Our work highlights the utility of CDPs as a diverse, easy-to-screen scaffold family worthy of inclusion in modern drug discovery strategies, demonstrated by the discovery of a candidate CNS drug delivery vehicle ready for further optimization and preclinical development.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Crook ZR,Girard E,Sevilla GP,Merrill M,Friend D,Rupert PB,Pakiam F,Nguyen E,Yin C,Ruff RO,Hopping G,Strand AD,Finton KAK,Coxon M,Mhyre AJ,Strong RK,Olson JM

doi

10.1016/j.jmb.2020.04.002

subject

Has Abstract

pub_date

2020-06-26 00:00:00

pages

3989-4009

issue

14

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(20)30279-5

journal_volume

432

pub_type

杂志文章

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