以核酸为作用靶的药物研究  

Studies on drug targeting to nucleic acids

作　　者：张礼和[1] 

机构地区：[1]北京大学天然药物及仿生药物国家重点实验室,北京100083

出　　处：《北京大学学报（医学版）》2002年第5期418-426,共9页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金重点项目 ( 2 92 3 2 0 2 0 ;2 963 2 0 60 );国家重点基础研究发展规划项目 ( 973 )基金 (G19980 5 110 3 )资助

摘　　要：The selective inhibition of expression of specific genes by oligonucleotides via an antisense or antigene strategy provides an attractive and elegant approach to drug discovery. Several requirements must be fulfilled by a potential antisense oligonucleotide including the improvements in their stability to nuclease digestion, in their ability to penetrate the cell membrane and in their efficient hybridization to the target RNA/DNA. Isonucleosides represent a novel class of carbohydrate modified nucleosides in which the nucleobase is linked to various positions of ribose other than C1’. The torsion angles in the sugar phosphate backbones of such oligonucleotides consisting of isonucleosides exhibit profound changes compared to regular oligonucleotides. These alternations in torsion angles might affect the recognition of such oligomers by nuclease. It could also be anticipated that the bases in the modified oligonucleotides retain their hybridization properties with complementary sequences. In the first part of this paper, we discussed the hybridization properties and enzymatic stability of oligonucleotides bearing such isonucleosides. It is reported that several types of peptides, such as nuclear transport signal sequence, viral fusion peptides, hydrophobic peptides, and signal peptides, have shown intrinsic ability to perturb cell membrane. It would be interesting to investigate whether such kinds of peptide conjugate could be used for the purpose of improving their cell membrane permeability. In the second and third part of this paper, we reported the synthesis and biological properties of antisense oligonucleotide conjugates. Finally, we described the formation of parallel intermolecular G quadruplex structure by isonucleoside.The selective inhibition of expression of specific genes by oligonucleotides via an antisense or antigene strategy provides an attractive and elegant approach to drug discovery. Several requirements must be fulfilled by a potential antisense oligonucleotide including the improvements in their stability to nuclease digestion, in their ability to penetrate the cell membrane and in their efficient hybridization to the target RNA/DNA. Isonucleosides represent a novel class of carbohydrate modified nucleosides in which the nucleobase is linked to various positions of ribose other than C1'. The torsion angles in the sugar phosphate backbones of such oligonucleotides consisting of isonucleosides exhibit profound changes compared to regular oligonucleotides. These alternations in torsion angles might affect the recognition of such oligomers by nuclease. It could also be anticipated that the bases in the modified oligonucleotides retain their hybridization properties with complementary sequences. In the first part of this paper, we discussed the hybridization properties and enzymatic stability of oligonucleotides bearing such isonucleosides. It is reported that several types of peptides, such as nuclear transport signal sequence, viral fusion peptides, hydrophobic peptides, and signal peptides, have shown intrinsic ability to perturb cell membrane. It would be interesting to investigate whether such kinds of peptide conjugate could be used for the purpose of improving their cell membrane permeability. In the second and third part of this paper, we reported the synthesis and biological properties of antisense oligonucleotide conjugates. Finally, we described the formation of parallel intermolecular G quadruplex structure by isonucleoside.

关 键 词：反义寡核苷酸类 药理学 核酸类 药物设计 化学 药物 

分 类 号：R962[医药卫生—药理学]