Variation of Tetrahydrofurans in Thyclotides Enhances Oligonucleotide Binding and Cellular Uptake of Peptide Nucleic Acids

被引：5
|
作者：
Zheng, Hongchao [1 ]
Clausse, Victor [1 ]
Amarasekara, Harsha [1 ]
Mazur, Sharlyn J. [2 ]
Botos, Istvan [3 ]
Appella, Daniel H. [1 ]
机构：
[1] NIDDK, Synthet Bioact Mol Sect, Lab Bioorgan Chem LBC, NIH, Bethesda, MD 20892 USA
[2] NCI, Lab Cell Biol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA
[3] NIDDK, Lab Mol Biol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA
来源：
JACS AU | 2023年 / 3卷 / 07期
关键词：
thyclotide; peptide nucleic acids (PNAs); bindingproperties; cell uptake; X-ray crystal structure; backbone modification; miR-21; inhibition; preorganization; ANTISENSE OLIGONUCLEOTIDES; CRYSTAL-STRUCTURE; PNA; DNA; DELIVERY; RECOGNITION; HELIX; THERMODYNAMICS; STABILITY; HYDRATION;
D O I：
10.1021/jacsau.3c00198
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
Selectiveincorporation of conformational constraintsinto thyclotidescan be used to modulate their binding to complementary oligonucleotides,increase polarity, and optimize uptake into HCT116 cells without assistancefrom moieties known to promote cell uptake. The X-ray structure andbiophysical studies of a thyclotide-DNA duplex reveal thatincorporation of tetrahydrofurans into an aegPNAbackbone promotes a helical conformation that enhances binding tocomplementary DNA and RNA. Selective incorporation of tetrahydrofuransinto the aegPNA backbone allows polarity to be increasedincrementally so that uptake into HCT116 cells can be optimized. Theenhanced binding, polarity, and cellular uptake properties of thyclotideswere used to demonstrate effective inhibition of microRNA-21 in HCT116cells.
引用
收藏
页码：1952 / 1964
页数：13
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