Minimally modified oligonucleotides - combination of end-capping and pyrimidine-protection.

The nuclease resistance of an oligonucleotide sequence that was phosphorothioate (PS)-modified in various positions and patterns was examined. We present a new ¿minimal' protection strategy for antisense oligonucleotides which is a combination of the end-capping technique and the protection of internal pyrimidine residues which are the major sites of endonuclease degradation. This strategy reduces the number of modifications needed to make a nuclease resistant oligonucleotide and therefore should minimize the non-sequence-specific effects that are frequently observed with uniformly modified oligonucleotides.