Nanotechnology

Scientists develop gene-silencing DNA enzymes that can target a single molecule

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May 09, 2023

(Nanowerk News) Researchers from the University of California, Irvine have developed a DNA enzyme – or DNAzyme – that can differentiate between two strands of RNA in cells and cut disease-related strands while leaving the healthy strands intact. This breakthrough “gene silencing” technology could revolutionize the development of DNAzim for treating cancer, infectious diseases and neurological disorders.

DNAzim are nucleic acid enzymes that cut other molecules. Through chemistry, the UCI team developed the Dz 46 enzyme, which specifically targets allele-specific RNA mutations in the KRAS gene, a key regulator of cell growth and division, which is found in 25 percent of all human cancers.

A description of how the team achieved this evolution of the enzyme was recently published in an online journal Nature Communications (“Chemical evolution of autonomous DNAzymes with allele-specific gene silencing activity”).

“Generating a DNAzyme that can function effectively under natural conditions of the cell system is more challenging than expected,” said co-author John Chaput, UCI professor of pharmaceutical sciences. “Our results show that chemical evolution can pave the way for the development of new therapies for a wide variety of diseases.”

Gene silencing has been available for more than 20 years and several FDA-approved drugs incorporate different 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 out specific gene mutations, offering patients innovative and precise drug treatments.

DNAzyme resembles the Greek letter omega and acts as a catalyst by speeding up chemical reactions. The “arms” on the left and right bind to the target region of the RNA. The loop binds the magnesium, and folds and cuts the RNA at very specific sites. But generating DNAzim with strong double-turn activity under physiological conditions requires ingenuity, because DNAzim are usually highly dependent on magnesium concentrations not found in human cells.

“We solved that problem by re-engineering the DNAzim using chemicals to reduce its dependence on magnesium and doing it in such a way that we can maintain high catalytic turnover activity,” said Chaput. “We are one of the first examples, if not the first, of achieving that. The next step is to advance the Dz 46 to a point where it is ready for pre-clinical trials.”

Team members Kim Thien Nguyen, project scientist, and Turnee N. Malik, postdoctoral scholar, both from the Department of Pharmaceutical Sciences, also participated in the study.

The researchers and UCI have filed a provisional patent application on the chemical composition and cleavage preference of Dz 46. Chaput is a consultant for drug development company 1E Therapeutics, which is supporting this work.



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