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DNAzymes

In general, DNAzymes are catalytically active DNA molecules. DNAzymes of the so-called 10-23 family are specifically characterized by their capability to cleave RNA molecules after appropriate binding. Thus, they directly exert RNA endonuclease activity. 10-23 DNAzymes are single-stranded DNA molecules that consist of two binding domains flanking a central catalytic domain. The latter is composed of 15 deoxynucleotides, the sequence of which is conserved throughout all molecules within this specific DNAzyme class. In contrast, the binding domains are variable and are designed to specifically bind the corresponding target mRNA of interest by Watson-Crick base-pairing.

After binding of a DNAzyme to the corresponding sequence in the target mRNA via the binding domains (step 1), the catalytic domain becomes active and directly cleaves the target mRNA molecule (step 2).

dnazyme_step1

dnazyme_step2

After successful cleavage of a target mRNA molecule, the DNAzyme-RNA-complex dissociates and the RNA cleavage products are further degraded by endogenous, intracellular enzymes. The DNAzyme molecule is then available for subsequent binding and cleavage of additional mRNA molecules (step 3).

dnazyme_step3

The consequence of mRNA degradation is that translation into protein is incapacitated and the reduction in functional protein results in an inhibition of all down-stream events. The enzymatic activity of DNAzymes is Mg2+-dependent, however, no additional endogenous co-molecules are required for the action of these molecules. This makes the activity of the DNAzyme independent of the endogenous molecular machinery of the cells. Thus, DNAzymes represent a particular class of antisense molecules combining the superior specificity of antisense molecules with an inherent catalytic activity which makes them an attractive tool for the specific interference with disease-causing molecules.

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