A research team led by the University of California, Irvine has designed an efficient new enzyme that can produce a synthetic genetic material called threose nucleic acid. The ability to synthesize artificial strands of TNA, which is inherently more stable than DNA, advances the discovery of potentially more powerful and precise therapeutic options to treat cancer and autoimmune, metabolic and infectious diseases.
An article recently published in Catalysis of nature describes how the team created an enzyme called 10-92 that achieves rapid and faithful synthesis of TNA, overcoming key challenges in previous enzyme design strategies. Increasingly approaching natural DNA synthesis capacity, 10-92 TNA polymerase facilitates the development of future TNA drugs.
DNA polymerases are enzymes that replicate the genomes of organisms by copying DNA precisely and efficiently. They play vital roles in biotechnology and healthcare, as seen in the fight against COVID-19, where they were crucial to the detection of pathogens and eventual treatment with the mRNA vaccine.
“This achievement represents an important milestone in the evolution of synthetic biology and opens exciting possibilities for new therapeutic applications by significantly narrowing the performance gap between natural and artificial enzyme systems,” said corresponding author John Chaput, professor of pharmaceutical sciences at UC Irvine. “Unlike DNA, the biostability of TNA allows it to be used in a much broader range of treatments, and the new 10-92 TNA polymerase will allow us to achieve that goal.”
The team produced the 10-92 TNA polymerase using a technique called homologous recombination, which rearranges polymerase fragments from related species of archaebacteria. Through repeated cycles of evolution, researchers identified polymerase variants with increasing activity, ultimately resulting in a variant that is within the range of natural enzymes.
“The medicines of the future could be very different from the ones we use today,” Chaput said. “TNA’s resistance to enzymatic and chemical degradation positions it as the ideal candidate for developing new treatments such as therapeutic aptamers, a promising class of drugs that bind to target molecules with high specificity. Engineering enzymes that facilitate the discovery of “New approaches could address limitations of antibodies, such as better tissue penetration, and potentially have an even greater positive impact on human health.”
Other members of the UC Irvine team were graduate students Victoria A. Maola, Eric J. Yik and Mohammad Hajjar; project scientist Nicholas Chim; and undergraduates Joy J. Lee, Kalvin K. Nguyen, Jenny V. Medina, Riley N. Quijano, Manuel J. Holguin and Katherine L. Ho, all from the Department of Pharmaceutical Sciences.
This work was supported by a grant from the National Science Foundation, under award MCB1946312. John Chaput, Victoria Maola and Eric Yik and the University of California, Irvine have filed a patent application (PCT/US24/1159) on the composition and activity of 10-92 TNA polymerase. The other authors declared no competing interests.