Perfluoroaryl Bicyclic Cell‐Penetrating Peptides for Delivery of Antisense Oligonucleotides,Angewandte Chemie International Edition

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Perfluoroaryl Bicyclic Cell‐Penetrating Peptides for Delivery of Antisense Oligonucleotides
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2018-03-14 , DOI: 10.1002/anie.201801167
Justin M Wolfe ₁ , Colin M Fadzen ₁ , Rebecca L Holden ₁ , Monica Yao ₂ , Gunnar J Hanson ₂ , Bradley L Pentelute ₁

Affiliation

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.

中文翻译：

用于递送反义寡核苷酸的全氟芳基双环细胞穿透肽

外显子跳跃反义寡核苷酸是治疗遗传性疾病的有效方法，但外显子跳跃活性需要这些大分子到达细胞核。虽然细胞穿透肽可以改善递送，但蛋白水解不稳定性常常限制功效。据推测，富含精氨酸的肽的双环化将提高其稳定性以及将寡核苷酸递送至细胞核的能力。介绍了两种利用半胱氨酸全氟芳基化化学合成富含精氨酸的双环肽的方法。然后，将双环肽与磷酸二酰胺吗啉寡核苷酸 (PMO) 共价连接，并测定外显子跳跃活性。全氟芳基环肽和双环肽将 PMO 活性比未缀合的 PMO 提高了大约 14 倍。相对于单环肽，双环肽表现出增加的蛋白水解稳定性，证明全氟芳基双环肽是有效且稳定的递送剂。

更新日期：2018-03-14

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