Jun 1, 2020

A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action

Journal of Controlled Release : Official Journal of the Controlled Release Society
Alexander KominKalina Hristova


The rate of transport of small molecule drugs across biological barriers, such as the blood-brain barrier, is often a limiting factor in achieving a therapeutic dose. One proposed strategy to enhance delivery across endothelial or epithelial monolayers is conjugation to cell-penetrating peptides (CPPs); however, very little is known about the design of CPPs for efficient transcellular transport. Here, we report on transcellular transport of a CPP, designated the CL peptide, that increases the delivery of small-molecule cargoes across model epithelium approximately 10-fold. The CL peptide contains a helix-like motif and a polyarginine tail. We investigated the effect of cargo, helix-like motif sequence, polyarginine tail length, and peptide stereochemistry on cargo delivery. We showed that there is an optimal helix-like motif sequence (RLLRLLR) and polyarginine tail length (R7) for cargo delivery. Furthermore, we demonstrated that the peptide-cargo conjugate is cleaved by cells in the epithelium at the site of a two-amino acid linker. The cleavage releases the cargo with the N-terminal linker amino acid from the peptide prior to transport out of the epithelium. These studies provide new insight into the sequence requirements for...Continue Reading

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Mentioned in this Paper

cyclopenta(c, d)pyrene
Small Molecule
Pharmacologic Substance
Helix-Turn-Helix Motifs
Molecular Stereochemistry
Transcytotic Pathways
Blood - Brain Barrier Anatomy

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