Oligonucleotides containing 2′- O -methyl-5-(1-phenyl-1,2,3-triazol-4-yl)uridines demonstrate increased affinity for RNA and induce exon-skipping in vitro

The nucleotide monomer containing the 1-phenyl-1,2,3-triazole group attached to the 5-position of 2′- O -methyluridine is hereby presented together with a derivative further substituted with a p-sulfonamide group on the phenyl ring. Both were conveniently synthesised, and synergistic effect of the modifications were demonstrated when introduced into oligonucleotides and hybridised to complementary RNA. The combination of stacking of the phenyltriazoles and the conformational steering from the 2′-OMe group gave thermally very stable duplexes. Exon skipping in the distrophin transcript using 20-mer 2′-OMePS sequences with two phenyltriazoles introduced in different positions with and without the sulfonamide demonstrated efficient exon skipping but at the same level as the 2′-OMePS reference ASO.