C‑Nucleosides Stabilize RNA by Reducing Nucleophilicity at 2'-OH
Dipanwita Banerjee1, Lu Xiao1, Pavitra S Thacker1
1Department of Chemistry, Stanford University, Stanford, California 94305, United States.
Abstract:
Nucleotides with a carbon substitution for heteroatoms are common in biological and therapeutic RNAs. Important examples include the C-nucleosides pseudouridine and N1-methylpseudouridine; these modifications were reported to slow the degradation of large RNAs, but the mechanism is unknown. We measured kinetics of spontaneous and enzymatic cleavage at a single bond of synthetically modified RNAs and found that carbon substitution markedly reduces strand cleavage rates in RNA by both mechanisms. Studies of nucleophilic acylation reactions of RNAs and small alcohols of varied pK a suggest that reduced inductive effects resulting from carbon substitution for electronegative atoms results in both higher pK a and lower nucleophilicity. The results provide insight into native transcriptome modifications as well as RNA therapies.
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