Synthesis of siRNAs containing carbocyclic nucleotides and the role of cyclopentane conformation in RNAi activity
Jayanta Kundu, Dhrubajyoti Datta, Masaaki Akabane-Nakata, Soham Mandal, Monika Krampert, Martin Egli, Muthiah Manoharan
TL;DR
Researchers modified siRNAs with carbocyclic nucleotides to improve gene silencing in cells and mice.
Contribution
A new method for enhancing RNAi activity through carbocyclic nucleotide modifications at siRNA termini.
Findings
Carbocyclic nucleotides at siRNA 5′ ends improved gene silencing compared to unmodified siRNAs.
3′-O-methyl carbocyclic analogues showed lower activity than other modifications.
Modifications were effective in both cell and mouse models.
Abstract
5′-(E)- and 5′-(Z)-vinylphosphonate carbocyclic DNA and 5′-(E)-vinylphosphonate 2′- and 3′-O-methyl carbocyclic RNAs were incorporated at 5′ termini of antisense strands of small interfering RNAs. All but the 3′-O-methyl carbocyclic analogue resulted in gene silencing activity better than the siRNA lacking a 5′ phosphate in cells and in mice. 5′-(E)- and 5′-(Z)-vinylphosphonate carbocyclic DNA and 5′-(E)-vinylphosphonate 2′- and 3′-O-methyl carbocyclic RNAs were incorporated at 5′ termini of antisense strands of small interfering RNAs.
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Taxonomy
TopicsDNA and Nucleic Acid Chemistry · RNA Interference and Gene Delivery · RNA and protein synthesis mechanisms