Figure 4.

Three generations of common nucleic acid modifications. First generation replaced phosphodiester (PO) backbone to phosphorothioate (PS) to enhance degradative resistance. Second generation includes modification of 2′ ribose into 2′-O-methyl (2′-OMe) and 2′-O-Methoxyethyl (2′-MOE), which are popular in gapmer synthesis. Third generation restricts conformational flexibility by introducing a methyl bridge between 2′-O and 4′ of ribose. Locked nucleic acid (LNA) and constraint ethyl (cET). Ribose moiety would be completely replaced with tricyclic DNA (tcDNA) or cyclohexene (CeDNA). Alternative modification was phosphorodiamidate morpholino oligomer (PMO). This neutral nucleic acid was described with an additional amine accompanied with phosphorodiamidate backbone.