Hofmeister A.
*
et al.
Sanofi, Frankfurt am Main, Germany
Small Interfering RNAs Containing Dioxane- and Morpholino-Derived Nucleotide Analogues Show Improved Off-Target Profiles and Chirality-Dependent In Vivo Knock-Down.
J. Med. Chem. 2022;
65: 13736-13752
DOI:
10.1021/acs.jmedchem.2c00873
Key words
nucleic acids - oligonucleotides - siRNA - nucleotide analogue
Significance
The authors describe the synthesis of novel dioxane- and morpholine-based nucleotide precursors. These nucleotides were incorporated at position 7 of an antisense strand leading to improved in vitro off-target profiles due to destabilization of the seed region.
Comment
Interestingly, the corresponding (2S, 2R) isomers of 1 and 2 also led to improved off-target profiles. However, significantly lower in vivo potencies were observed, potentially due to the inability of these nucleosides to undergo Watson–Crick base paring.
