As illustrated during the pandemic, mRNA-based therapeutics and vaccines a new hope in the fight against diseases.
mRNA transports the most valuable cellular information—the chemical blueprint for the production of proteins—from the nucleus into the cytoplasm. As soon as mRNA has delivered its message to the protein-producing factories in the cytoplasm it is no longer needed and degraded by exonucleases. Depending on how long the mRNA remains in the cytoplasm, more or less of a protein is —be it health-promoting or disease-causing.
Now, researchers at the Max Planck Institute of Molecular Physiology have developed a strategy to extend the lifespan of mRNA by protecting it from its dismantling. Their study was published in Angewandte Chemie.
In a process called deadenylation, the target mRNA is recruited by RNA-binding proteins to the protein complex CCR4-NOT, which removes one adenine after the other. This is where the scientists’ new strategy comes in. Based on the structure of the mRNA-binding protein, the team developed a large peptide that can block the interaction of the CCR4-NOT complex with the target mRNA. However, large peptides have problems crossing cellular barriers. But, by revealing the 3D-structure of the peptide-inhibitor bound to the target, the chemists were able to make modifications that improved the cell permeability of the peptide.
In tests, treating cells with the peptide stabilized the polyadenine tails of two potential health promoting proteins: a tumor suppressor, which could have beneficial effects in cancer, and a nuclear receptor, whose increasing levels could help to treat various ageing-related diseases.
“The concept of stabilizing beneficial mRNAs by blocking their deadenylation has not yet been explored. Since almost all mRNAs undergo this process, blocking them can be used to develop new drugs that offer a new way to treat diseases where other strategies have failed”, says Peter ‘t Hart. His group is currently working on the development of further inhibitors against other components of the deadenylation machinery.