Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2'-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10% of the CFTR gene mutations are stop mutations that generate a premature termination codon (PTC), thus synthesizing a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, which is the ribosome's capacity to skip a PTC, thus generating a full-length protein. TRIDs are molecules exerting ribosome readthrough; for some, the mechanism of action is still under debate. We investigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their readthrough activity by in silico analysis and in vitro studies. Our results suggest a likely inhibition of FTSJ1, a tryptophan tRNA-specific 2'O-methyltransferase.

Automated summary

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene, leading to the synthesis of truncated CFTR protein. Ribosome readthrough, which bypasses premature termination codons (PTCs), can generate full-length protein. In this study, we investigated the potential mechanism of action of our synthesized TRIDs (NV848, NV914, and NV930) using in silico analysis and in vitro studies, and found a likely inhibition of FTSJ1, a specific 2'O-methyltransferase for tryptophan tRNA.