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Effects of Conformational Alteration Induced by D-/L-Isonucleoside Incorporation in siRNA on Their Stability in Serum and Silencing Activity
Huang, Ye1; Chen, Zhuo1; Chen, Yue1; Zhang, Hao1; Zhang, Yichao2; Zhao, Yilei2; Yang, Zhenjun1; Zhang, Lihe1
刊名BIOCONJUGATE CHEMISTRY
2013-06-01
DOI10.1021/bc300642u
24期:6页:951-959
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemical Research Methods ; Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary ; Chemistry, Organic
研究领域[WOS]Biochemistry & Molecular Biology ; Chemistry
关键词[WOS]SMALL INTERFERING RNA ; GUIDE STRAND SELECTION ; THERMODYNAMIC STABILITY ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; MAMMALIAN-CELLS ; ENZYME COMPLEX ; HUMAN DICER ; PAZ DOMAIN ; IN-VITRO
英文摘要

We report here that all of the D- or L-isonucleoside (isoNA) modified siRNAs investigated showed the characteristic A-form conformation in the circular dichroism (CD) spectra compared to native siRNA. The D-isoNA modification had less influence on the thermal stability of siRNAs, but all L-isoNA modification displayed a significant tendency to decrease the thermal stability of siRNA. It was also found that the stabilities of D-/L-isoNA modified siMek1 in serum were different and D-isoNA modification was more potent, i.e., increase of serum stability of siRNA, than L-isoNA modification. When D-isoNA incorporated at position 4 and position 5 at antisense strand of siMek1 showed obvious improvement on serum stability, however, L-isoNA incorporated at positions 11 and 12 at antisense strand and position 9 at sense strand made the siMek1 duplex formed very unstable in serum. The silencing activities of modified siMek1s with D-/L-isoNA at position 1 of antisense strand also dropped dramatically; however, the modification at 3′-terminal of the sense strand with D- or L-isoNA significantly enhanced the silencing activity targeting the antisense strand as reporter and minimized the passenger strand-specific off-target effect. IsoNA modified in the seed area of siMek1, siMek1 A04D and siMek1 A05L, showed similar activity to the native one and better target selectivity. In the case of modification at the position near the cleavage area, it was found that D- or L-isoNA modified sense strand at position 8, 9, or 15 of siMek1 could retain the silencing activities targeting the antisense strand as reporter. Especially, both siMek1 S15D and siMek1 S15L showed good silencing activity and high target selectivity compared to native siMek1. The effects of conformational alteration of such isoNA modification of siRNA on their stability in serum and silencing activity are discussed based on computer simulation. Systematic investigation of the relationship between modified siRNA conformation and their physical and biological properties should provide a useful guideline for chemical modification and optimization of siRNA for further clinical application.

语种英语
WOS记录号WOS:000320898900014
引用统计
被引频次:15[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/51990
专题北京大学药学院
北京大学医学部管理机构_后勤处
北京大学药学院_药物化学系
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, State Key Lab Microbial Metab, Shanghai 200030, Peoples R China
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GB/T 7714
Huang, Ye,Chen, Zhuo,Chen, Yue,et al. Effects of Conformational Alteration Induced by D-/L-Isonucleoside Incorporation in siRNA on Their Stability in Serum and Silencing Activity[J]. BIOCONJUGATE CHEMISTRY,2013,24(6):951-959.
APA Huang, Ye.,Chen, Zhuo.,Chen, Yue.,Zhang, Hao.,Zhang, Yichao.,...&Zhang, Lihe.(2013).Effects of Conformational Alteration Induced by D-/L-Isonucleoside Incorporation in siRNA on Their Stability in Serum and Silencing Activity.BIOCONJUGATE CHEMISTRY,24(6),951-959.
MLA Huang, Ye,et al."Effects of Conformational Alteration Induced by D-/L-Isonucleoside Incorporation in siRNA on Their Stability in Serum and Silencing Activity".BIOCONJUGATE CHEMISTRY 24.6(2013):951-959.
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