Identification of New Translational Readthrough Inducing Drugs

Genetic disease can be caused by mutations, that leads to a change in the DNA sequence which can affect one gene or more, or alteration in the chromosome structure. Among different mutation types, a nonsense mutation produces a premature stop codon (PTC) in the mRNA, leading to an impairment of genetic product synthesis [1]. In particular, the presence of a PTC induce a decrease in cytosolic mRNA levels, as a consequence of NMD surveillance mechanism activation, and production of a truncated and non-functional protein. This condition most of the time leads to the onset of clinical condition like cystic fibrosis (CF), Duchenne Muscular dystrophy (DMD), Leber’s Congenital Amaurosis (LCB) and Primary Immunodeficiency Regulatory Disorder (PIRD), just to cite few , and more broadly it’s estimated that approximately 11% of genetic disease and 12% of tumor suppressor gene mutations are caused by nonsense mutation underscoring the crucial importance of developing a treatment.[2] A novel treatment strategy for nonsense mutation is based on a pharmacological approach via molecules capable to induce the read-through of the PTC , known as TRIDs. The goal of this work is the identification of new TRIDs from the optimisation of the validated leads: NV848, NV914, NV930[3].