Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates

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Abstract
Triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phophonate (2) was coupled to the 5'' terminus of oligodeoxynucleotides via hydrogen phosphonate solid support DNA synthesis methodology. Duplex DNA oligomers with a single 5''-phospholipid melted at lower temperatures than the corresponding unmodified duplex, but duplexes bearing lipids at each 5'' end had higher Tms. In uptake experiments with L929 cells, 8-10 times more lipid-DNA became cell-associated than did unmodified DNA. Unmodified antisense diesters were inactive in a VSV antiviral assay in L929 cells (at up to 200 .mu.M). Attachment of a lipid to the oligomer, however, led to a > 90% at 150 .mu.M (> 80% at 100 .mu.M) reduction in viral protein synthesis. The antiviral activity depended on the sequence of the oligodeoxynucleotide, but some compounds having little or no base complementarity to the viral target were also effective. Phosphorothioate derivatives reduced viral protein synthesis by 20-30% at 100 .mu.M in the VSV assay. The lipid-DNA compounds were not toxic to the cells at up to 100 .mu.M.