Development of a new method to produce chemically modified mRNA

In a recent study, the research group of the Institute for Organic Chemistry of the University of Cologne led by Prof. Dr. Stephanie Kath-Schorr describes a new method for the enzymatic production of synthetic messenger RNA (mRNA). While natural base modifications of mRNA are already used – for example by BioNTech/Pfizer for the production of their coronavirus vaccine – this newly developed mRNA additionally contains non-natural nucleotides introduced specifically at the site. Nucleotides are molecules that function as the basic building blocks of RNA. This new approach using unnatural nucleotides allows scientists to study how mRNA is introduced into cells and observe how newly introduced information propagates at the cellular level. This in turn promises better long-term therapeutic applications. The article ‘Stronger together for in cell translation: natural and unnatural base modified mRNA’ appeared in chemical sciences.

Previous methods did not allow the production of mRNAs with chemically modified building blocks at specific positions because mRNAs are produced enzymatically due to their length of several thousand building blocks. In the new method, the researchers use a so-called “extended genetic alphabet” when enzymatically transcribing DNA into RNA. Where normally two base pairs are responsible for transcription, the team introduced a third base pair. This allowed them to introduce unnatural RNA nucleotides into specific mRNA segments, alter protein production, and study cellular application in detail.

“We investigated the stability of this chemically modified mRNA in cells, whether the artificially produced mRNA can be used in cells as a template for efficient protein production, and what influence chemical modifications have on protein production,” he said. said Kath-Schorr. The results show that the new method is very powerful for monitoring the introduction of mRNA into cells, and for monitoring and influencing its spread at the cellular level as well as the efficiency of information transcription. This opens new possibilities for developing effective mRNA therapies – not only as vaccines, but also in the treatment of cancer.

In principle, the method could be applied to any mRNA. However, this requires further research, which is currently being planned in cooperation with the University Hospital of Cologne. In a later stage, clinical studies should be conducted. Kath-Schorr’s team is also currently developing a more efficient method to package mRNAs before introducing them into cells. In this field, the Institute of Organic Chemistry cooperates with other scientists from the Department of Chemistry as well as with the Faculty of Medicine within the framework of the UoC Forum ‘Transformative Nanocarriers for RNA Transport and Tracking – Advanced Concepts for Therapy and Diagnostics’ (iRNA carriers).

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Material provided by University of Cologne. Note: Content may be edited for style and length.

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