Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides
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 bi...
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| Format: | Article |
| Language: | English |
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Wiley
2020
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| Online Access: | https://hdl.handle.net/1721.1/123522 |
| _version_ | 1811085149499031552 |
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| author | Wolfe, Justin Fadzen, Colin M. Holden, Rebecca Lynn Yao, Monica Hanson, Gunnar J. Pentelute, Bradley L. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Wolfe, Justin Fadzen, Colin M. Holden, Rebecca Lynn Yao, Monica Hanson, Gunnar J. Pentelute, Bradley L. |
| author_sort | Wolfe, Justin |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:03:22Z |
| format | Article |
| id | mit-1721.1/123522 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:03:22Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1235222022-10-01T12:50:24Z Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides Wolfe, Justin Fadzen, Colin M. Holden, Rebecca Lynn Yao, Monica Hanson, Gunnar J. Pentelute, Bradley L. Massachusetts Institute of Technology. Department of Chemistry General Chemistry Catalysis 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. National Science Foundation (U.S.) (Grant 1122374) National Institute of Child Health and Human Development (U.S.) (Grant F30HD093358) 2020-01-22T16:30:22Z 2020-01-22T16:30:22Z 2018-02 2020-01-02T18:52:42Z Article http://purl.org/eprint/type/JournalArticle 1433-7851 1521-3773 https://hdl.handle.net/1721.1/123522 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 en http://dx.doi.org/10.1002/anie.201801167 Angewandte Chemie International Edition Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | General Chemistry Catalysis Wolfe, Justin Fadzen, Colin M. Holden, Rebecca Lynn Yao, Monica Hanson, Gunnar J. Pentelute, Bradley L. Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title | Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title_full | Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title_fullStr | Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title_full_unstemmed | Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title_short | Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides |
| title_sort | perfluoroaryl bicyclic cell penetrating peptides for delivery of antisense oligonucleotides |
| topic | General Chemistry Catalysis |
| url | https://hdl.handle.net/1721.1/123522 |
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