Sugar boost: when ribose modifications improve oligonucleotide performance.

Abstract

Since the first antisense oligonucleotides were described, synthetic oligonucleotides have been used to modulate gene expression for numerous research and therapeutic purposes over the last 30 years. In order to improve the performance of oligonucleotides in therapeutic applications, various chemical modifications of nucleotides have been developed and applied to antisense, antigen, aptamer and short interfering RNA (siRNA) therapeutics. For example, backbone substitution of phosphodiester bonds to create DNA phosphorothioates and 4'-thio RNA analogs, increases resistance to nuclease degradation. Modifications to improve the activity of oligonucleotides by 2'-O-modification of the ribose sugar, and the systematic approaches used to evaluate the potential of mixed oligonucleotides, are discussed in this review. Although structural data from crystallization studies appear to confirm observed gains in thermodynamic stability with 2'-O-modifications, no simple rules can be drawn to predict the overall effect of individual modifications for the rational design of mixed oligonucleotides.