A frequently utilized approach in mRNA medicine development focuses on eliminating harmful mRNA. In contrast, the stabilization of beneficial mRNA remains a substantial hurdle. However, a research team has successfully addressed this issue, creating the first compound that prevents mRNA deadenylation and thereby halts its degradation.
mRNA-based treatments and vaccines are now seen as a promising avenue in the battle against terminal illnesses. The conventional method in creating messenger RNA (mRNA) treatments involves targeting and destroying mRNA linked to diseases. Meanwhile, stabilizing mRNA that supports health is still a formidable challenge. The group led by Peter ‘t Hart at the Chemical Genomics Centre of the Max Planck Institute for Molecular Physiology has risen to this challenge by devising the inaugural active substance that obstructs the deadenylation process of mRNA and prevents its breakdown. This research serves as a solid foundation for developing novel mRNA-centered therapies and offers biologists tools to gain deeper insights into mRNA degradation mechanisms.
mRNA carries essential cellular information—the chemical instructions vital for protein production—from the nucleus to the cytoplasm. Once mRNA delivers its content to the protein synthesis machinery in the cytoplasm, it becomes unnecessary and is broken down by exonucleases. The duration for which mRNA remains in the cytoplasm directly influences the quantity of protein synthesized—whether beneficial or detrimental. Adjusting mRNA levels presents a key strategy within the burgeoning domain of RNA-based therapies.
Strategies to Safeguard the Messenger
The team led by Peter ‘t Hart has introduced a novel approach to prolong the existence of mRNA by safeguarding it from degradation. Naturally, mRNA is not very durable and would disintegrate prematurely if not for molecular caps shielding its ends. The 3’ end of mRNA possesses a polyadenine tail, which is typically around 200 nucleotides long. Nevertheless, this protective mechanism has a limited lifespan—mRNA’s average half-life is only about 7 hours. During deadenylation, RNA-binding proteins target the mRNA and attach it to a protein complex known as CCR4-NOT, which systematically removes adenine nucleotides. This is where the researchers’ innovative strategy comes into play. They utilized the mRNA-binding protein’s structure to design a large peptide that can hinder the CCR4-NOT complex’s interaction with the target mRNA. However, large peptides face challenges in crossing cellular barriers, which is crucial for their potential therapeutic use. By elucidating the 3D structure of the peptide-inhibitor complex with the target, the chemists were able to modify the compound, enhancing its ability to penetrate cells.
Enhancing the Stability of Beneficial Proteins
The scientists took their research a step further by showcasing their strategy’s effectiveness in cellular assays. Applying the peptide to cells resulted in the stabilization of the polyadenine tails of two promising health-related proteins: one being a tumor suppressor that may positively influence cancer outcomes, and the other a nuclear receptor that could potentially aid in addressing various age-related diseases. ‘t Hart noted, “The idea of preserving beneficial mRNAs by obstructing their deadenylation is still relatively uncharted. Since this process affects nearly all mRNAs, inhibiting it could lead to the creation of new medicines to tackle issues previously resistant to other therapeutic methods.” His team is currently focused on developing additional inhibitors targeting other components of the deadenylation process.
