Scientists have overcome a major challenge in developing messenger RNA (mRNA) therapeutics, which are being explored as a promising treatment for incurable diseases. A team led by Peter ‘t Hart at the Max Planck Institute of Molecular Physiology has created the first active substance that inhibits mRNA deadenylation, preventing its degradation.
Current mRNA-based therapies destroy disease-causing mRNA but leave health-promoting mRNA intact. The new substance stabilizes this health-promoting mRNA by blocking its interaction with an enzyme called CCR4-NOT, which removes adenine from the polyadenine tail at the 3’ end of mRNA. This tail normally degrades mRNA over time.
The researchers developed a peptide inhibitor that targets the CCR4-NOT complex and improved its cell permeability through computer simulations and structural analysis. In cellular assays, they demonstrated the potential of this strategy by stabilizing polyadenine tails of tumor suppressor and nuclear receptor mRNAs.
“The concept of stabilizing beneficial mRNAs by blocking their deadenylation has not yet been explored,” says ‘t Hart. “Blocking them can be used to develop new drugs that offer a new way to treat diseases where other strategies have failed.” The team is currently working on developing further inhibitors against the deadenylation machinery.
This breakthrough could lead to innovative mRNA-based therapeutics and provide valuable insights into the regulation of mRNA levels, which is a key strategy in RNA-based therapeutics.
Source: https://phys.org/news/2024-10-mrna-stabilizing-substance-aid-therapeutics.html