Consecutive 5'- and 3'-amide linkages stabilise antisense oligonucleotides and elicit an efficient RNase H response.

Antisense oligonucleotides are now entering the clinic for hard-to-treat diseases. New chemical modifications are urgently required to enhance their drug-like properties. We combine amide coupling with standard oligonucleotide synthesis to assemble backbone chimera gapmers that trigger an efficient RNase H response while improving serum life time and cellular uptake.