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bioRxiv · 10.1101/2021.11.09.467859

2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases

Bidou, L.·Bugaud, O.·Merer, G.·Coupet, M.·Hatin, I.·Chirkin, E.·Francois, P.·Cintrat, J.-C.·Namy, O.
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Abstract

Premature termination codons (PTCs) account for 10% to 20% of genetic diseases in humans. The gene inactivation resulting from PTC can be counteracted by the use of drugs stimulating PTC readthrough, thereby restoring production of the full-length protein. However, a greater chemical variety of readthrough inducers is required to broaden the medical applications of this therapeutic strategy. In this study, we developed a new reporter cell line and performed high-throughput screening (HTS) to identify potential new readthrough inducers. After three successive assays, we isolated 2-guanidino-quinazoline (TLN468). We assessed the clinical potential of this drug as a potent readthrough inducer on the 40 PTCs most frequently responsible for Duchenne muscular dystrophy. We found that TLN468 was more efficient than gentamicin, and acted on a broader range of sequences, without inducing the readthrough of natural stop codons.

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Bidou, L., Bugaud, O., Merer, G., Coupet, M., Hatin, I., Chirkin, E., Francois, P., Cintrat, J.-C., Namy, O.. 2021-11-11. 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases. https://doi.org/10.1101/2021.11.09.467859

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