Stapled Peptides as Inhibitors of mRNA Deadenylation

Therapeutic intervention targeting mRNA typically aims at reducing the levels of disease-causing sequences. Achieving the opposite effect of blocking the destruction of beneficial mRNA remains underexplored. The degradation of mRNA starts with the removal of poly(A) tails, reducing their stability and translational activity, which is mainly regulated by the CCR4-NOT complex. The subunit NOT9 binds various RNA binding proteins, that recruit mRNA in a sequence-specific manner to the CCR4-NOT complex to promote their deadenylation. These RNA binding proteins interact with NOT9 through a helical NOT9 binding motif, which we used as a starting point for development of the hydrocarbon stapled peptide NIP-2. The peptide (K