Only recently, a new era in medicine began with the first RNA vaccines. These modified RNAs trigger immune responses in the human immune system. Another approach in RNA medicine targets the body’s own RNA and its protein modulators with specifically tailored active substances.
– Peng WuThe first small-molecule inhibitors against the RNA-modifying enzyme METTL16 have been developed by the research group leader at the Chemical Genomics Centre at the Max Planck Institute of Molecular Physiology in Dortmund, and colleagues. METTL16 is a methyltransferase responsible for regulating different RNAs and is a potential target for anti-cancer treatment. These new findings provide a basis for a more comprehensive study of METTL16’s role in health and disease, bringing us closer to the development of therapeutic agents that target RNA modifiers.
RNA has long been considered only as a passive messenger in tThe cell uses RNA to transfer genetic information from DNA to the ribosomes, where proteins are produced. However, it has been discovered that RNA has additional functions beyond this. In addition to coding DNA, there is non-coding DNA that regulates cellular processes by controlling gene activity. There are now at least twelve identified classes of RNA, including RNAi, which the cell uses to silence genes by degrading specific RNA targets, particularly when fighting foreign viral DNA. RNA interacts with a variety of biomolecules, performing a range of functions.The importance of RNA, DNA, proteins, and metabolites in regulating vital cellular processes cannot be understated. Errors in these regulatory complexes can lead to the development of diseases. RNA undergoes chemical modifications that impact its stability, structure, and interactions, ultimately determining its fate. Over 170 different RNA modifications have been identified, with the most common being methylation on the N6-position of the RNA-nucleotide adenosine (m6A). This modification enables cells to rapidly adapt to changes in their environment by triggering appropriate cellular responses, such as division, differentiation, or migration. Therefore, understanding and studying RNA-methylation is essential.The process of methylation in RNA is tightly controlled by a group of proteins: “writers” that deposit, “readers” that recognize, and “erasers” that remove the methyl group.
New substance prevents writing to RNA
Abnormal RNA methylation has been linked to cancer and other human diseases, making “writers” a promising target for therapy. Only a few RNA m6A writers have been discovered so far, and only potent inhibitors for METTL3 have been reported. These inhibitors prevent the writer from utilizing the biomolecule S-adenosyl methionine (SAM) as ink. Peng Wu’s group has now identified the first inhibitor of the wri.The researchers discovered a new inhibitor of METTL16 called ter METTL16, which operates differently from previously known inhibitors by blocking the interaction between METTL16 and RNA. They identified this inhibitor by creating an assay that measures the disruption between METTL16 and a mRNA substrate labeled with a fluorophore.
Some cancer cells have higher levels of writer and are more susceptible to reduced SAM levels, making them potential targets for anticancer treatment. However, the specific biological effects of METTL16’s binding to RNA substrates have not been fully determined. This research lays the groundwork for better understanding these consequences.Peng Wu stated that the study of METTL16’s role in disease and health is not only important for further research, but also for the creation of new RNA-targeting treatments. The journal reference for this study is Yang Liu, Georg L. Goebel, Laurin Kanis, Oguz Hastürk, Claus Kemker, Peng Wu. “Aminothiazolone Inhibitors Disrupt the Protein–RNA Interaction of METTL16 and Modulate the m6A RNA Modification” in JACS Au, 2024; DOI: 10.1021/jacsau.3c00832.