Gene silencing can be achieved by introducing into cells a short "antisense oligonucleotide" that is complementary to an RNA target. This experiment was first done by Zamecnik and Stephenson in 1978 and continues to be a useful approach, both for laboratory experiments and potentially for clinical applications (antisense therapy). Several viruses, such as influenza viruses Respiratory syncytial virus (RSV) and SARS coronavirus (SARS-CoV), have been targeted using antisense oligonucleotides to inhibit their replication in host cells.
If the antisense oligonucleotide contains a stretch of DNA or a DNA mimic (phosphorothioate DNA, 2′F-ANA, or others) it can recruit RNase H to degrade the target RNA. This makes the mechanism of gene silencing catalytic. Double-stranded RNA can also act as a catalytic, enzyme-dependent antisense agent through the RNAi/siRNA pathway, involving target mRNA recognition through sense-antisense strand pairing followed by target mRNA degradation by the RNA-induced silencing complex (RISC). The R1 plasmid hok/sok system provides yet another example of an enzyme-dependent antisense regulation process through enzymatic degradation of the resulting RNA duplex.
Other antisense mechanisms are not enzyme-dependent, but involve steric blocking of their target RNA (e.g. to prevent translation or to induce alternative splicing). Steric blocking antisense mechanisms often use oligonucleotides that are heavily modified. Since there is no need for RNase H recognition, this can include chemistries such as 2′-O-alkyl, peptide nucleic acid (PNA), locked nucleic acid (LNA), and Morpholino oligomers.