Green Manufacturing Breakthrough: Chemoenzymatic Synthesis of Pseudouridine Triphosphate Cuts mRNA Vaccine Costs

In the research and development of mRNA drugs, the efficient preparation of modified nucleotides is critical to determining the cost and accessibility of pharmaceutical products. A research team led by Martin Pfeiffer and Bernd Netzky from Graz University of Technology has published a study in Angewandte Chemie, proposing an integrated chemoenzymatic synthetic route that provides a new green solution for the large-scale production of pseudouridine triphosphate (ΨTP) and N¹-methylpseudouridine triphosphate (m¹ΨTP).

The study efficiently synthesizes the precursor pseudouridine monophosphate via enzymatic cascade reactions. Combined with chemical methylation and a novel kinase cascade phosphorylation technique, it achieves high-yield synthesis of the target products. Compared with traditional purely chemical routes, the new process shortens the synthesis steps of m¹ΨTP from six to four, significantly improving atomic economy and sustainability indicators. Notably, the phosphorylation system constructed using Saccharomyces cerevisiae UMPK and Escherichia coli AcK yields a final product purity of 98% and eliminates the use of toxic reagents.

As a core raw material for mRNA vaccines, the high cost of m¹ΨTP has long been an industry bottleneck. This technological breakthrough not only lowers production barriers but also lays a solid process foundation for the widespread application of future vaccines against cancers and infectious diseases.

FOR DETAIL：https://pmc.ncbi.nlm.nih.gov/articles/PMC12363647/

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