Thyclotides, tetrahydrofuran-modified peptide nucleic acids that efficiently penetrate cells and inhibit microRNA-21

被引:8
作者
Clausse, Victor [1 ]
Zheng, Hongchao [1 ]
Amarasekara, Harsha [1 ]
Kruhlak, Michael [2 ]
Appella, Daniel H. [1 ]
机构
[1] NIDDK, Synthet Bioact Mol Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA
[2] NCI, Microscopy Core Facil, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
IN-VIVO; ANTISENSE ACTIVITY; CELLULAR DELIVERY; TUMOR-SUPPRESSOR; PNA; CANCER; EXPRESSION; MIRNA; GENE; DNA;
D O I
10.1093/nar/gkac864
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Peptide nucleic acids (PNAs) are promising therapeutic molecules for gene modulation; however, they suffer from poor cell uptake. Delivery of PNAs into cells requires conjugation of the PNA to another large molecule, typically a cell-penetrating peptide or nanoparticle. In this study, we describe a new PNA-based molecule with cyclic tetrahydrofuran (THF) backbone modifications that in some cases considerably improve cell uptake. We refer to these THF-PNA oligomers as thyclotides. With THF groups at every position of the oligomer, the cell uptake of thyclotides targeted to miR-21 is enhanced compared with the corresponding unmodified PNA based on an aminoethylglycine backbone. An optimized thyclotide can efficiently enter cells without the use of cell-penetrating peptides, bind miR-21, its designated microRNA target, decrease expression of miR-21 and increase expression of three downstream targets (PTEN, Cdc25a and KRIT1). Using a plasmid with the PTEN-3 ' UTR coupled with luciferase, we further confirmed that a miR-21-targeted thyclotide prevents miR-21 from binding to its target RNA. Additionally, the thyclotide shows no cytotoxicity when administered at 200 times its active concentration. We propose that thyclotides be further explored as therapeutic candidates to modulate miRNA levels.
引用
收藏
页码:10839 / 10856
页数:18
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