2-Guanidino-quinazoline promotes efficient translational suppression of nonsense mutations responsible of Human genetic diseases

Premature translation termination (PTC) codons account for 10%-20% of genetic diseases in humans. To counteract the gene inactivation by a PTC, it is possible to use drugs to stimulate PTC readthrough, restoring the expression of the full-length protein. To broaden the medical applications of this therapeutic strategy it is important to increase the chemical variety of readthrough-inducers. In the present study we have developed a new reporter cell-line and performed a High Throughput Screening (HTS). Using a workflow of three successive assays we have isolated the 2-Guanidino-quinazoline (TLN468) as a potent readthrough inducer. We tested the clinical potential of the drug onto the 40 most frequent PTC responsible for Duchenne muscular dystrophy and show that TLN468 is more efficient and acts on a broader range of sequences than gentamicin without inducing readthrough of natural stop codons. Overall design: RiboSeq of three replicates of Hela cells in presence of DMSO, G418 or TLN468, to identify potential stop codon readthrough induced by TLN468. RNASeq of three replicates of Hela cells in presence of DMSO, G418 or TLN468, to identify potential stop codon readthrough induced by TLN468.