Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides
Author(s)
Wolfe, Justin; Fadzen, Colin M.; Holden, Rebecca Lynn; Yao, Monica; Hanson, Gunnar J.; Pentelute, Bradley L.; ... Show more Show less
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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.
Date issued
2018-02Department
Massachusetts Institute of Technology. Department of ChemistryJournal
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
ISSN
1433-7851
1521-3773
Keywords
General Chemistry, Catalysis