1134031-93-8Relevant articles and documents
5′-C-Malonyl RNA: Small Interfering RNAs Modified with 5′-Monophosphate Bioisostere Demonstrate Gene Silencing Activity
Zlatev, Ivan,Foster, Donald J.,Liu, Jingxuan,Charisse, Klaus,Brigham, Benjamin,Parmar, Rubina G.,Jadhav, Vasant,Maier, Martin A.,Rajeev, Kallanthottathil G.,Egli, Martin,Manoharan, Muthiah
, p. 953 - 960 (2016)
5′-Phosphorylation is a critical step in the cascade of events that leads to loading of small interfering RNAs (siRNAs) into the RNA-induced silencing complex (RISC) to elicit gene silencing. 5′-Phosphorylation of exogenous siRNAs is generally accomplished by a cytosolic Clp1 kinase, and in most cases, the presence of a 5′-monophosphate on synthetic siRNAs is not a prerequisite for activity. Chemically introduced, metabolically stable 5′-phosphate mimics can lead to higher metabolic stability, increased RISC loading, and higher gene silencing activities of chemically modified siRNAs. In this study, we report the synthesis of 5′-C-malonyl RNA, a 5′-monophosphate bioisostere. A 5′-C-malonyl-modified nucleotide was incorporated at the 5′-terminus of chemically modified RNA oligonucleotides using solid-phase synthesis. In vitro silencing activity, in vitro metabolic stability, and in vitro RISC loading of 5′-C-malonyl siRNA was compared to corresponding 5′-phosphorylated and 5′-nonphosphorylated siRNAs. The 5′-C-malonyl siRNAs showed sustained or improved in vitro gene silencing and high levels of Ago2 loading and conferred dramatically improved metabolic stability to the antisense strand of the siRNA duplexes. In silico modeling studies indicate a favorable fit of the 5′-C-malonyl group within the 5′-phosphate binding pocket of human Ago2MID domain.
5'-END DERIVATIVES
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Paragraph 0556; 0557, (2014/01/07)
The present invention provides compounds of formula (1). Another aspect of the invention relates to a method of inhibiting the expression of a gene in call, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.
