Discovery of the first RNA m6A activator compounds


Chemical modifications of RNA provide an additional epitranscriptomic level of control over cellular functions. N-6-methylated adenosines (m6As) are found in several types of RNA and their amounts are regulated by methyltransferases and demethylases.

One of the most important enzymes catalyzing generation of m6A on mRNA is the trimer N-6-methyltransferase METTL3-14-WTAP complex. Its activity has been linked to such critical biological processes as cell differentiation, proliferation and death.

We used in silico-based discovery to identify small-molecule ligands that bind to METTL3-14-WTAP and determined experimentally their binding affinity and kinetics, as well as their effect on enzymatic function. We showed that these ligands serve as activators of the RNA N6-adenosine (m6A) methylation.

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