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

Alejandro Gimenez Molina; Prithi Raguraman; Line Delcomyn; Rakesh N Veedu; Poul Nielsen

doi:10.1016/j.bmc.2021.116559

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

Bioorg Med Chem. 2022 Feb 1:55:116559. doi: 10.1016/j.bmc.2021.116559. Epub 2021 Dec 12.

Authors

Alejandro Gimenez Molina¹, Prithi Raguraman², Line Delcomyn¹, Rakesh N Veedu³, Poul Nielsen⁴

Affiliations

¹ Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5230 Odense M, Denmark.
² Centre for Molecular Medicine and Innovative therapeutics, Murdoch University, Perth 6150, Australia; Perron Institute for Neurological and Translational Science, Perth 6009, Australia.
³ Centre for Molecular Medicine and Innovative therapeutics, Murdoch University, Perth 6150, Australia; Perron Institute for Neurological and Translational Science, Perth 6009, Australia. Electronic address: R.Veedu@murdoch.edu.au.
⁴ Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5230 Odense M, Denmark. Electronic address: pouln@sdu.dk.

PMID: 34999527
DOI: 10.1016/j.bmc.2021.116559

Abstract

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.

Keywords: Antisense Oligonucleotides; Click Chemistry; RNA targeting; π-π-stacking.