Building oligonucleotide therapeutics using non-natural chemistries

Modified nucleotides are increasingly being utilized in all categories of therapeutic oligonucleotides to increase nuclease-resistance, target affinity and specificity. The extent to which these substitutions are tolerated varies with the different modes of action exploited by various modalities, but fully modified oligonucleotides have now been discovered for most types of therapeutic oligonucleotide. Fully phosphorothioate-substituted antisense oligonucleotides have been used for several years. The first fully modified siRNA was reported in 2006 with a 2′-O-methyl sense strand and a phosphorothioate antisense strand. The first fully modified aptamer (2′-O-methyl) was reported in 2005. It is expected that future candidate therapeutic oligonucleotides will have even more drug-like characteristics as a result of the inclusion of modified nucleotides.