Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides
Name
nihms-1511674.pdf
Description
Accepted version
Size
690.94 KB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Wolfe, Justin
Fadzen, Colin M.
Holden, Rebecca Lynn
Yao, Monica
Hanson, Gunnar J.
Pentelute, Bradley L.
Date Issued
February 2018
Journal
Angewandte Chemie International Edition
Publisher
Wiley
Citation
Wolfe, Justin M. et al. "Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides." Angewandte Chemie International Edition 57, 17 (February 2018): 4756 © 2018 Wiley
Version
Author's final manuscript
Abstract
Exon-skipping antisense oligonucleotides are effective treatments for genetic diseases, yet exon-skipping activity requires that these macromolecules reach the nucleus. While cell-penetrating peptides can improve delivery, proteolytic instability often limits efficacy. It is hypothesized that the bicyclization of arginine-rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Two methods were introduced for the synthesis of arginine-rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides were covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improved PMO activity roughly 14-fold over the unconjugated PMO. The bicyclic peptides exhibited increased proteolytic stability relative to the monocycle, demonstrating that perfluoroaryl bicyclic peptides are potent and stable delivery agents.
Subjects
General Chemistry
Catalysis
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1002/anie.201801167
