8YNP

RNA duplex containing Methylformamide

Summary for 8YNP

• Entry DOI: 10.2210/pdb8ynp/pdb
• Related: 8YNO
• Descriptor: RNA (5'-R(*GP*GP*AP*CP*(5BU)P*CP*GP*AP*GP*(HHX)P*CP*C)-3') (2 entities in total)
• Functional Keywords: methylformamide, rna
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 7894.57

Authors

Kondo, J.,Abe, H. (deposition date: 2024-03-11, release date: 2025-01-22)

Primary citation

Nomura, K.,An, S.,Kobayashi, Y.,Kondo, J.,Shi, T.,Murase, H.,Nakamoto, K.,Kimura, Y.,Abe, N.,Ui-Tei, K.,Abe, H.
Synthesis of 2'-formamidonucleoside phosphoramidites for suppressing the seed-based off-target effects of siRNAs.
Nucleic Acids Res., 52:10754-10774, 2024

PubMed Abstract: In this study, we report the synthesis of 2'-formamidonucleoside phosphoramidite derivatives and their incorporation into siRNA strands to reduce seed-based off-target effects of small interfering RNAs (siRNAs). Formamido derivatives of all four nucleosides (A, G, C and U) were synthesized in 5-11 steps from commercial compounds. Introducing these derivatives into double-stranded RNA slightly reduced its thermodynamic stability, but X-ray crystallography and CD spectrum analysis confirmed that the RNA maintained its natural A-form structure. Although the introduction of the 2'-formamidonucleoside derivative at the 2nd position in the guide strand of the siRNA led to a slight decrease in the on-target RNAi activity, the siRNAs with different sequences incorporating 2'-formamidonucleoside with four kinds of nucleobases into any position other than 2nd position in the seed region revealed a significant suppression of off-target activity while maintaining on-target RNAi activity. This indicates that 2'-formamidonucleosides represent a promising approach for mitigating off-target effects in siRNA therapeutics.

PubMed: 39231537
DOI: 10.1093/nar/gkae741

Experimental method

X-RAY DIFFRACTION (1.4 Å)