Mechanism-Based Discovery of New TRIDs Targeting Ribosome Pockets

Approximately 10% of all human pathogenic mutations are nonsense mutations which give rise to premature termination codon (PTC) diseases, leading to an estimated 35 million people worldwide who harbor such mutations. To date, no approaches leading to medical treatments which increase PTC readthrough have received FDA approval. However, one well-tolerated translation readthrough inducing drug (TRID), ataluren, was conditionally approved for 11 years by the European Medicines Agency for treatment of nonsense mutation Duchenne Muscular Dystrophy. In recent work we have shown that ataluren increases readthrough indirectly, by exclusively inhibiting termination without directly affecting readthrough by suppressor aminoacyl-tRNAs (sup-aa-tRNAs). Based on the idea that this mode of action (MoA) might be the reason for ataluren's low toxicity, we have discovered potential new TRIDs, which target pockets within the ribosome to which the termination factor eRF1 binds but sup-aa-tRNAs do not. These new TRIDs, dipeptide derivatives of eRF1 and some Sartans, mimic ataluren's MoA. Three Sartans, which are angiotensin II receptor blockers and FDA-approved for treatment of hypertension, are significantly more potent than ataluren in our reconstituted in vitro readthrough assay. These compounds might, right now, be more effective than ataluren in treating some PTC diseases. We anticipate that further development of these lead compounds will lead to more general effectiveness, used both alone and in combination with other classes of readthrough inducers.