RNA basic building blocks – biocatalytically produced

Person wearing medical gloves draws a vaccine from an ampoule with a syringe.

Researchers from TU Graz and acib succeed in the first enzyme-driven biocatalytic synthesis of nucleic acid building blocks. This facilitates the development of antiviral agents and RNA-based therapeutics. Due to the COVID 19 pandemic and the associated intensive search for therapeutics and vaccines, the chemical substance class of nucleosides is experiencing an enormous increase in interest. Natural and synthetic nucleosides have an antiviral effect and can act as building blocks of ribonucleic acids (RNA). When incorporated into RNA, novel interactions within the macromolecule result with positive consequences for stability and biological effectiveness.

In medicinal chemistry, the molecular family of carbon (C)-nucleosides is particularly in demand. These differ from the naturally more frequently occurring nitrogen (N)-nucleosides – the classical building blocks of RNA – in the way the sugar is linked to the so-called nucleic base. Instead of a carbon-nitrogen bond, C-nucleosides have a carbon-carbon bond. This is biochemically much more stable and gives active ingredients a longer biological half-life. For the first time, researchers from Graz University of Technology and acib have now succeeded in biocatalytically producing C-nucleosides with the help of enzymes. The concrete results have been published in Nature Communications. The scientists discovered and characterized in a study the enzyme “YeiN”, which can link the two nucleoside building blocks ribose-5-phosphates and uracil by means of a specific carbon bond. They are the first researchers worldwide to demonstrate an enzyme that is a suitable biocatalyst for the production of C-nucleosides.

Efficient and eco-friendly production

With the help of the catalytic power of “YeiN”, the Graz-based company was able to produce several derivatives of the important C-nucleoid pseudouridine. They were also able to show that one of these derivatives can be incorporated into RNA and thus enable the modification of RNA. This is particularly relevant for the production of RNA-based therapeutic products, as the incorporation of pseudouridine into the RNA increases stability and half-life and thus improves the effectiveness of therapeutic RNA, such as a vaccine. In their study, the scientists show that pseudouridine can be produced biocatalytically. Compared to a purely chemical synthesis, this is a much more efficient way, since fewer reaction steps and no toxic chemicals are required. The biocatalytic production of C-nucleosides is therefore a very strong, elegant alternative to classical chemical synthesis and even superior to it in terms of efficiency. Based on the published findings, research can now be conducted to expand the substrate spectrum of “YeiN” for the biocatalytic synthesis of further relevant C-nucleosides.

RNA vaccines

The first comprehensive vaccinations against COVID-19 with RNA vaccines has already begun. These completely novel vaccines contain genetic information of the pathogen and induce cells to produce a viral protein, which is then presented to the immune system. The subsequent immune reaction protects the body from an actual virus infection. If one is already infected with the virus, antiviral drugs can prevent the virus from multiplying.

The C-nucleoside based drug Remdesivir has these necessary antiviral properties and is effective against a number of RNA viruses, including corona and ebola viruses. The active ingredient has received conditional approval in the EU for the treatment of COVID-19 patients. The biocatalytic production of C-nucleosides could provide further impetus for this new hope as well as RNA vaccines based on C-nucleosides.

Picture credits: Pixabay

This work is based on the following scientific publication:
Martin Pfeiffer, Bernd Nidetzky: Reverse C-glycosidase reaction provides C-nucleotide building blocks of xenobiotic nucleic acids.

Nature Communications, December 2020. DOI: 10.1038/s41467-020-20035-0