Inhibition of HSV-1 proliferation by decoy phosphodiester oligonucleotides containing ICP4 recognition sequences

Transcriptional control in eukaryotes results from the interplay between DNA sequences in promoters, enhancers, or silencers and transcription factors. Selective control of gene expression can thus be achieved by inhibiting specific transcription factor/DNA interactions. Transcriptional activity of DNA binding transcription factors can be inhibited by competition with double-stranded oligonucleotides (decoys) that contain their specific recognition sequences. The immediate early protein ICP4 of herpes simplex virus type 1 (HSV-1) is a sequence-specific DNA binding protein that is essential for viral replication. We synthesized double-stranded hairpin phosphodiester oligonucleotides carrying ICP4 sites and demonstrated their ability to specifically titrate ICP4. Upon addition to Vero cells, ICP4 hairpin decoys significantly reduced HSV-1 titers (IC50 = 0.3 microM), whereas a control hairpin oligonucleotide had no activity. Antiviral activity of ICP4 hairpin decoys was correlated to their relative binding affinities. These results show that phosphodiester oligonucleotides can compete for binding of specific transcription factors within cells, thus providing a potential therapeutic tool to control disease-causing genes.