2'-O-[2-[2-(N,N-二甲基氨基)乙氧基]乙基]修饰的寡核苷酸：电荷相互作用因素与立体电子效应的共生关系

2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modified oligonucleotides: symbiosis of charge interaction factors and stereoelectronic effects.

作者信息

Prhavc Marija, Prakash Thazha P, Minasov George, Cook P Dan, Egli Martin, Manoharan Muthiah

机构信息

Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.

出版信息

Org Lett. 2003 Jun 12;5(12):2017-20. doi: 10.1021/ol0340991.

DOI:10.1021/ol0340991

PMID:12790517

Abstract

[structure: see text] Oligonucleotides with a novel, 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE) modification have been synthesized. This modification, a cationic analogue of the 2'-O-(2-methoxyethyl) (2'-O-MOE) modification, exhibits high binding affinity to target RNA (but not to DNA) and exceptional resistance to nuclease degradation. Analysis of the crystal structure of a self-complementary oligonucleotide containing a single 2'-O-DMAEOE modification explains the importance of charge factors and gauche effects on the observed antisense properties. 2'-O-DMAEOE modified oligonucleotides are ideal candidates for antisense drugs.

摘要

[结构：见正文] 已合成了具有新型2'-O-[2-[2-(N,N-二甲基氨基)乙氧基]乙基]（2'-O-DMAEOE）修饰的寡核苷酸。这种修饰是2'-O-(2-甲氧基乙基)（2'-O-MOE）修饰的阳离子类似物，对靶RNA（而非DNA）表现出高结合亲和力，并且对核酸酶降解具有出色的抗性。对含有单个2'-O-DMAEOE修饰的自互补寡核苷酸的晶体结构分析解释了电荷因素和扭转效应对于所观察到的反义特性的重要性。2'-O-DMAEOE修饰的寡核苷酸是反义药物的理想候选物。