Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides.
Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides.
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DOI：
10.1002/anie.201801167
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发表时间：
2018-04-16
期刊：
影响因子：
--
通讯作者：
Pentelute BL
中科院分区：
文献类型：
--
作者：
Wolfe JM;Fadzen CM;Holden RL;Yao M;Hanson GJ;Pentelute BL
跳过外显子的反义寡核苷酸是治疗遗传病的有效方法，然而跳过外显子的活性需要这些大分子到达细胞核。虽然穿透细胞的多肽可以改善药物的传递，但蛋白质分解的不稳定性往往限制了疗效。我们假设，富含精氨酸的多肽的自行车化将提高它们的稳定性，并提高它们将寡核苷酸送入细胞核的能力。在这里，我们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，将双环肽共价连接到磷二酰吗啉寡核苷酸(PMO)上，并检测其外显子跳跃活性。全氟芳基环肽和双环肽提高了PMO的活性，大约是未结合PMO的14倍。与单环相比，双环肽具有更高的蛋白质降解稳定性，表明全氟芳基双环肽是一种有效且稳定的递送剂。跳过外显子的反义寡核苷酸是治疗遗传病的有效方法，然而跳过外显子的活性需要这些大分子到达细胞核。虽然穿透细胞的多肽可以改善药物的传递，但蛋白质分解的不稳定性往往限制了疗效。我们假设，富含精氨酸的多肽的自行车化将提高它们的稳定性，并提高它们将寡核苷酸送入细胞核的能力。在这里，我们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，将双环肽共价连接到磷二酰吗啉寡核苷酸(PMO)上，并检测其外显子跳跃活性。全氟芳基环肽和双环肽提高了PMO的活性，大约是未结合PMO的14倍。与单环相比，双环肽具有更高的蛋白质降解稳定性，表明全氟芳基双环肽是一种有效且稳定的递送剂。利用半胱氨酸全氟芳基化化学合成了多肽自行车。与单环肽相比，双环肽显示出更高的蛋白分解稳定性。此外，在与反义寡核苷酸结合后，双环肽结合物的细胞活性比未结合的寡核苷酸增加了14倍。
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. We hypothesized that bicyclization of arginine-rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Here, we introduce two methods for the synthesis of arginine-rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides are covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improve 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. 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. We hypothesized that bicyclization of arginine-rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Here, we introduce two methods for the synthesis of arginine-rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides are covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improve 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. Peptide bicycles are synthesized using cysteine perfluoroarylation chemistry. The bicyclic peptides demonstrate enhanced proteolytic stability relative to the monocyclic peptide. Additionally, after conjugation to antisense oligonucleotides, the bicyclic peptide conjugates exhibit a 14-fold increase in cellular activity when compared to the unconjugated oligonucleotide.
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影响因子：
15
作者：
Spokoyny, Alexander M.;Zou, Yekui;Ling, Jingjing J.;Yu, Hongtao;Lin, Yu-Shan;Pentelute, Bradley L.
通讯作者：
Pentelute, Bradley L.
影响因子：
15
作者：
Lian, Wenlong;Jiang, Bisheng;Qian, Ziqing;Pei, Dehua
通讯作者：
Pei, Dehua
影响因子：
14.8
作者：
Heinis, Christian;Rutherford, Trevor;Winter, Greg
通讯作者：
Winter, Greg
由未保护肽的精确调控多重环化开发的肽大环化合物
影响因子：
4.3
作者：
Wang, Jinghui;Zha, Mirao;Wu, Chuanliu
通讯作者：
Wu, Chuanliu
影响因子：
3.2
作者：
Chen, Shiyu;Morales-Sanfrutos, Julia;Heinis, Christian
通讯作者：
Heinis, Christian