Making RNA Molecules – University of Innsbruck

Schematic representation of different chemical conformations of RNA molecules.

Ribonucleic acid (RNA) plays an important role in basic research, biotechnology and biomedicine. The group led by Ronald Mikura of the Institute of Organic Chemistry is one of the world's leading groups in chemical RNA synthesis. In an overview article International Edition of Applied Chemistry Discuss recent developments in this area.

The importance of ribonucleic acid (RNA) arises not only from its function as an intermediary between DNA and proteins, but also from its role in gene regulation, developmental biology, and disease. Many properties of RNA depend on its ability to undergo chemical modifications that affect its stability and function. In basic research, RNA is a valuable tool for studying and understanding cellular mechanisms and molecular signaling pathways.

In medicine, RNA is used for vaccines and therapeutic approaches. RNA-based vaccines, such as those against the coronavirus, exploit the molecule's ability to encode antigenic proteins, thereby triggering immune responses against pathogens. Likewise, RNA therapies offer a targeted approach to treating diseases by modifying gene expression. In the laboratory, RNA is usually produced by in vitro transcription (IVT), in which RNA is produced from DNA templates using polymerases. IVT is a particularly selective method for long RNAs (>200 nucleotides). For short RNAs (<100 nucleotides), chemical synthesis has been established as a precise method for generating RNA sequences and structures that allow the addition of site-specific (natural or synthetic) modifications.

An overview of recent developments

In Innsbruck, Ronald Mikura's group at the Institute of Organic Chemistry distinguished itself as one of the world's leading research groups in the field of chemical RNA synthesis. FWF Special Research Area RNA-Deco. In a recent review article in the journal Angewandte Chemie International Edition, they discuss recent advances in the field and initiate new safety concepts as part of ongoing efforts to overcome current quantitative limitations.

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We pursue selective modifications that are more challenging to incorporate into RNA. These include RNA containing deazapurine nucleosides required for nuclear mutation, as well as xanthosine, acetylcytidine, 5-hydroxymethylcytidine, 3-methylcytidine, 2-isothiocyanidation, 2'-isothiofluorification, to elucidate the kinetic aspects of catalytic RNAs. Recent advances in purely chemical synthesis of 5'-capped mRNAs and enzymatic ligation of chemically synthesized oligoribonucleotides to yield long RNA with various modifications required for single-molecule fluorescence (FRET) studies are also presented. Finally, the authors highlight promising advances in RNA-catalyzed RNA modification using cofactors that confer biosynthetic functions.

The RNA research results of Ronald Mikura's group described in the article were funded by the Austrian Science Fund FWF, the Center for Molecular Biology at the University of Innsbruck (CMBI) and the research funding agency FFG.

Output: Chemical synthesis of modified RNA. Lauren Flemich, Raphael Periter and Ronald Mikura. Angew. Chem. Int. Ed. (2024) DOI: 10.1002/any.202403063

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