RESEARCH
Nicolas Cornelissen
Biocatalysis and Chemical Biology
Chemo-enzymatic synthesis of nucleotides and nucleic acids
We are interested in the chemo-enzymatic synthesis of modified nucleotides, enzyme engineering and the biological evaluation of modified nucleic acids, such as mRNA, in mammalian cells.
Modified nucleotides are important building blocks for a wide variety of nucleic acid-based therapeutics, including siRNAs, ASOs and mRNA. Although nucleotides have been synthesised for decades, simple, fast and environmentally friendly methods are urgently needed. Our chemo-enzymatic approach combines the organic synthesis of nucleoside-5′-monophosphates (NMPs) with the efficient enzymatic phosphorylation of promiscuous polyphosphate kinases, generating the corresponding nucleoside-5′-triphosphates (NTPs).
Engineering of polyphosphate kinases provides access to variants with a broad substrate spectrum. We have demonstrated that these enzymes can be applied for the synthesis of various base-modified ATP and GTP analogues.
The poly(A) tail is a hallmark of eukaryotic mRNAs and plays a pivotal role in the translation initiation and stability. We can generate hyper-modified poly(A) tails (100-1000 nucleotides) and aim to elucidate the structure-function relationship of the poly(A) tail in mammalian cells. This will inform the design of the next generation of mRNA therapeutics.
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