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

Author:

Carollo Pietro Salvatore1,Tutone Marco1ORCID,Culletta Giulia1ORCID,Fiduccia Ignazio1,Corrao Federica1,Pibiri Ivana1ORCID,Di Leonardo Aldo1ORCID,Zizzo Maria Grazia1ORCID,Melfi Raffaella1ORCID,Pace Andrea1ORCID,Almerico Anna Maria1,Lentini Laura1ORCID

Affiliation:

1. Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, University of Palermo, 90128 Palermo, Italy

Abstract

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.

Funder

European Union-NextGenerationEU

Italian Cystic Fibrosis Research Foundation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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