Cellular Uptake and Cytosolic Delivery of a Cyclic Cystine Knot Scaffold.
Cellular Uptake and Cytosolic Delivery of a Cyclic Cystine Knot Scaffold.
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DOI：
10.1021/acschembio.0c00297
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发表时间：
2020-06-19
影响因子：
4
通讯作者：
Wang CK
中科院分区：
文献类型：
--
作者：
Yin H;Huang YH;Deprey K;Condon ND;Kritzer JA;Craik DJ;Wang CK
环肽是一类结构非常稳定的大环肽，已被报道可以穿透细胞，使其成为将抑制性多肽输送到靶向细胞内蛋白的支架材料。然而，到目前为止，人们对它们的细胞摄取和胞浆定位知之甚少，这限制了它们的治疗潜力。在这项研究中，最近发展的氯烷烃渗透试验与已建立的方法相结合，以表征原型环肽Kalata B1的细胞摄取和胞质递送。我们发现卡拉塔B1以较低的效率进入胞浆。环6中残基的构效关系研究表明，一些修饰，如增加阳离子残基含量，不影响递送效率，而另一些修饰，包括引入单一疏水氨基酸，确实显著改善了胞液递送。我们的结果为进一步开发一类结构独特的支架提供了基础，用于将治疗货物输送到细胞中。
Cyclotides are macrocyclic peptides with exceptionally stable structures and have been reported to penetrate cells, making them promising scaffolds for the delivery of inhibitory peptides to target intracellular proteins. However, their cellular uptake and cytosolic localization have been poorly understood until now, which has limited their therapeutic potential. In this study, the recently developed chloroalkane penetration assay was combined with established assays to characterize the cellular uptake and cytosolic delivery of the prototypic cyclotide, kalata B1. We show that kalata B1 enters the cytosol at low efficiency. A structure–activity study of residues in loop 6 showed that some modifications, such as increasing cationic residue content, did not affect delivery efficiency, whereas others, including introducing a single hydrophobic amino acid, did significantly improve cytosolic delivery. Our results provide a foundation for the further development of a structurally unique class of scaffolds for the delivery of therapeutic cargoes into cells.
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