A research team led by the University of California, Irvine has engineered an efficient new enzyme that can produce a synthetic genetic material called threose nucleic acid. The ability to synthesize artificial chains of TNA, which is inherently more stable than DNA, advances the discovery of potentially more powerful, precise therapeutic options to treat cancer and autoimmune, metabolic and infectious diseases.
A paper recently published in Nature Catalysis describes how the team created an enzyme called 10-92 that achieves faithful and fast TNA synthesis, overcoming key challenges in previous enzyme design strategies. Inching ever closer to the capability of natural DNA synthesis, the 10-92 TNA polymerase facilitates the development of future TNA drugs.
DNA polymerases are enzymes that replicate organisms’ genomes by accurately and efficiently copying DNA. They play vital roles in biotechnology and healthcare, as seen in the fight against COVID-19, in which they were crucial to pathogen detection and eventual treatment using the mRNA vaccine.
“This achievement represents a major milestone in the evolution of synthetic biology and opens up exciting possibilities for new therapeutic applications by significantly narrowing the performance gap between natural and artificial enzyme systems,” said corresponding author John Chaput, UC Irvine professor of pharmaceutical sciences. “Unlike DNA, TNA’s biostability allows it to be used in a much broader range of treatments, and the new 10-92 TNA polymerase will enable us to reach 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, the researchers identified polymerase variants with increasing activity, ultimately resulting in a variant that’s within the range of natural enzymes.
“Drugs of the future could look very different than those we use today,” Chaput said. “TNA’s resilience to enzymatic and chemical degradation positions it as the ideal candidate for developing new treatments such as therapeutic aptamers, a promising drug class that binds to target molecules with high specificity. Engineering enzymes that facilitate the discovery of new approaches could address the limitations of antibodies, such as improved tissue penetration, and potentially have an even greater positive impact on human health.”
Other UC Irvine team members 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 the 10-92 TNA polymerase. The other authors declared no competing interests.
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