The MOE Modification of RNA: Origins and Widescale Impact on the Oligonucleotide Therapeutics Field

Abstract

AbstractIn an article published by Helvetica Chimica Acta in 1995, chemist P. Martin describes the synthesis of 2′‐O‐alkylated ribonucleosides for use in therapeutic antisense oligonucleotides (ASOs). This work was motivated by the need for a modified ribose structure that was compatible with solid‐phase synthesis protocols and that, when incorporated into an oligonucleotide, would render it resistant to nucleases without attenuating its ability to hybridize to a complementary RNA target. Martin described a robust route to 2′‐O‐alkylribonucleosides in which the ribose 2′‐OH group is substituted with 2′‐ethylene glycol derivatives. Oligonucleotides containing these modifications displayed überraschende Eigenschaften – ‘surprising properties’ – notably, higher affinity and specificity for RNA substrates and greater stability to nucleases relative to their unmodified counterparts. Today, the 2′‐ethylene glycol modification is universally known in the field as the 2′‐O‐methoxyethyl (MOE) modification. The chemistry features in four ASO drugs and many others in clinical trials. Here, we 1) summarize the synthesis of the MOE‐modified ribose; 2) outline the properties of MOE‐modified oligonucleotides as reported in Martin’s article; 3) highlight the first approved MOE‐modified ASO drugs, mipomersen and nusinersen; and 4) survey MOE‐modified ASOs in clinical development. In the outlook, we put these developments into context and consider future possibilities for the MOE modification.