San Diego (California) [US], May 10 : A DNA enzyme, or DNAzyme, has been created by researchers at the University of California, Irvine that can identify between two RNA strands inside a cell and cut the one linked to the sickness while leaving the healthy strand unharmed. This ground-breaking "gene silencing" method may fundamentally alter how DNAzymes are created and used to treat neurological illnesses, infectious diseases, and cancer.
Nucleic acid enzymes called DNAzymes are used to cut other molecules. The Dz 46 enzyme, created by UCI's team through chemistry, particularly targets the allele-specific RNA mutation in the KRAS gene, the principal regulator of cell growth and division, which can be detected in 25% of all cases of human cancer. In the online journal Nature Communications, a description of how the team accomplished this enzyme development was only recently published.
"Generating DNAzymes that can effectively function in the natural conditions of cell systems has been more challenging than expected," said corresponding author John Chaput, UCI professor of pharmaceutical sciences. "Our results suggest that chemical evolution could pave the way for development of novel therapies for a wide range of diseases."
Gene silencing has been available for more than 20 years and some FDA-approved drugs incorporate various versions of the technology, but none can distinguish a single point mutation in an RNA strand. The benefit of the Dz 46 enzyme is that it can identify and cut a specific gene mutation, offering patients an innovative, precision medicine treatment.
The DNAzyme resembles the Greek letter omega and acts as a catalyst by accelerating chemical reactions. The "arms" on the left and right bind to the target region of the RNA. The loop binds to magnesium, and folds and cuts the RNA at a very specific site. But generating DNAzymes with robust multiple turnover activity under physiological conditions required some ingenuity, because DNAzymes are normally very dependent on concentrations of magnesium not found inside a human cell.
"We solved that problem by re-engineering the DNAzyme using chemistry to reduce its dependency on magnesium and did so in such a way that we could maintain high catalytic turnover activity," Chaput said. "Ours is one of the very first, if not the first, example of achieving that. The next steps are to advance Dz 46 to a point that it's ready for pre-clinical trials."
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