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Synfacts 2023; 19(01): 0087
DOI: 10.1055/s-0042-1752379
DOI: 10.1055/s-0042-1752379
Innovative Drug Discovery and Development
Novel Dioxane- and Morpholino Nucleotide Analogues with Improved Off-Target Profiles in siRNAs
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.
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.
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.
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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.
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Publication History
Article published online:
16 December 2022
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