Theoretically, short synthetic "antisense" oligodeoxynucleotides, complementary in sequence to viral mRNA, might be able to inhibit viral gene expression. For example, hybridization to viral mRNA might prevent the splicing, transport, or translation of that mRNA, or render it susceptible to degradation by RNase H. On the other hand, hybridization to viral DNA or cDNA might block transcription or replication, or block the attachment of DNA-binding regulatory proteins. Short single-stranded DNA sequences of this sort have displayed antiviral activity against HIV, HSV, and influenza viruses in cultured cells, but there are major problems with the specificity, stability, and uptake of oligodeoxynucleotides. Statistically, the genome of the average human contains no sequence precisely complementary to any random oligonucleotide of 18 or more bases. In practice, however, significant binding occurs even if there are one or two mismatches, and nonspecific binding to proteins has also been demonstrated. Moreover, oligonucleotides are rapidly degraded by extracellular and intracellular nucleases unless the backbone of the molecule is modified to circumvent this problem. Third, the uptake of oligonucleotides into cells is very inefficient; attempts are being made to facilitate entry, for example, by coupling to a hydrophobic peptide or lipid.
An avant-garde variation on this theme is to produce transgenic plants or animals that constitutively make antisense RNA or a ribozyme (RNA with RNase activity specific for a particular nucleotide sequence). Some such transgenic plants and animals display resistance to the virus in question. Clearly, transgenic humans are a fantasy, but the current commercial interest in creating plants and animals that are resistant to microbial disease may well benefit research on antisense oligonucleotides as antiviral agents in humans.
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