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

作者：He, Junlin; Zhang, Di; Wang, Qi; Wei, Xia; Cheng, Maosheng^*; Liu, Keliang

来源：Organic and Biomolecular Chemistry, 2011, 9(16): 5728-5736.

DOI：10.1039/c1ob05065f

• RNA CLEAVAGE ACTIVITY
• CATALYTIC CORE
• DNA ENZYME
• INHIBITION
• DEOXYRIBOZYMES
• EXPRESSION
• RIBOZYMES
• SELECTION
• GROWTH
• VIRUS

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.

• 单位
  沈阳药科大学