Zheng Hongchao, Clausse Victor, Amarasekara Harsha, Mazur Sharlyn J, Botos Istvan, Appella Daniel H
Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry (LBC), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, 8 Center Drive, Room 404, Bethesda, Maryland 20892, United States.
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, United States.
JACS Au. 2023 Jun 29;3(7):1952-1964. doi: 10.1021/jacsau.3c00198. eCollection 2023 Jul 24.
Selective incorporation of conformational constraints into thyclotides can be used to modulate their binding to complementary oligonucleotides, increase polarity, and optimize uptake into HCT116 cells without assistance from moieties known to promote cell uptake. The X-ray structure and biophysical studies of a thyclotide-DNA duplex reveal that incorporation of tetrahydrofurans into an PNA backbone promotes a helical conformation that enhances binding to complementary DNA and RNA. Selective incorporation of tetrahydrofurans into the PNA backbone allows polarity to be increased incrementally so that uptake into HCT116 cells can be optimized. The enhanced binding, polarity, and cellular uptake properties of thyclotides were used to demonstrate effective inhibition of microRNA-21 in HCT116 cells.
将构象限制选择性地引入硫代环核苷酸可用于调节它们与互补寡核苷酸的结合、增加极性，并在没有已知促进细胞摄取的部分的帮助下优化其进入HCT116细胞的摄取。硫代环核苷酸-DNA双链体的X射线结构和生物物理研究表明，将四氢呋喃引入肽核酸主链可促进螺旋构象，增强与互补DNA和RNA的结合。将四氢呋喃选择性地引入肽核酸主链可使极性逐步增加，从而优化其进入HCT116细胞的摄取。利用硫代环核苷酸增强的结合、极性和细胞摄取特性，证明了其对HCT116细胞中微小RNA-21的有效抑制作用。
