Modification of oligonucleotides with weak basic residues via the 2′-O-carbamoylethyl linker for improving nuclease resistance without loss of duplex stability and antisense activity†,10.1039/C9OB00668K

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Modification of oligonucleotides with weak basic residues via the 2′-O-carbamoylethyl linker for improving nuclease resistance without loss of duplex stability and antisense activity†

Yoshiaki Masaki,Keishi Yamamoto,Keita Yoshida,Atsuya Maruyama,Takahito Tomori,Yusuke Iriyama,Hiroyuki Nakajima,Tatsuro Kanaki,Kohji Seio

Organic & Biomolecular Chemistry Pub Date : 04/29/2019 00:00:00 , DOI:10.1039/C9OB00668K

Abstract

For the improvement of nuclease resistance, four kinds of new modifications through a carbamoylethyl linker were designed. Among them, the 2′-O-[2-N-{2-(benzimidazol-1-yl)ethyl}carbamoylethyl] modification showed 20-fold longer half-life when treated with a 3′ to 5′ exonuclease compared to the 2′-O-methoxyethyl (MOE) modification, which is used in approved drugs. In addition, this large modification did not disturb the binding affinity or RNase H-dependent antisense activity. From these findings, it could be concluded that an adequate linker, such as carbamoylethyl in this study, could extend the utility of 2′-O-modification without loss of the properties of nucleic acids. This strategy would be useful for the development of nucleic acid therapeutics.