A novel strategy of chemical modification for rate enhancement of 10-23 DNAzyme: a combination of A9 position and 8-aza-7-deaza-2′-deoxyadenosine analogs

被引:24
作者
He, Junlin [2 ]
Zhang, Di [1 ]
Wang, Qi [2 ]
Wei, Xia [2 ]
Cheng, Maosheng [1 ]
Liu, Keliang [2 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China
[2] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China
基金
中国国家自然科学基金;
关键词
RNA CLEAVAGE ACTIVITY; CATALYTIC CORE; DNA ENZYME; INHIBITION; DEOXYRIBOZYMES; EXPRESSION; RIBOZYMES; SELECTION; GROWTH; VIRUS;
D O I
10.1039/c1ob05065f
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
With the help of a divalent-metal ion, 10-23 DNAzyme cleaves RNA. Chemical modification of its catalytic loop to make a more efficient enzyme has been a challenge. Our strategy started from its five 2'-deoxyadenosine residues (A5, A9, A11, A12, and A15) in the loop based on the capability of the N7 atom to form hydrogen bonds in tertiary structures. 8-Aza-7-deaza-2'-deoxyadenosine and its analogs with 7-substituents (3-aminopropyl, 3-hydroxylpropyl, or phenethyl) were each used to replace five dA residues, respectively, and their effect on cleavage rate were evaluated under single-turnover conditions. The results indicated that the N7 atom of five dA residues were necessary for catalytic activity, and the N8 atom and 7-substituents were detrimental to the catalytic behavior of 10-23 DNAzyme, except that all these modifications at A9 were favourable for the activity. Especially, DZ-3-9 with 7-(3-aminopropyl)-8-aza-7-deaza-2'-deoxyadenosine (3) at A9 position gave a 12-fold increase of k(obs), compared to the corresponding parent 10-23 DNAzyme. DZ-3-9 was supposed to catalyze the cleavage reaction with the same mechanism as 10-23 DNAzyme based on their very similar pH-dependent and divalent metal ions-dependent cleavage patterns. Introduction of functional groups at A9 position was demonstrated to be a successful and feasible approach for more efficient 10-23 DNAzyme analogs.
引用
收藏
页码:5728 / 5736
页数:9
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