beta-Cyclodextrin derivatives as carriers to enhance the antiviral activity of an antisense oligonucleotide directed toward a coronavirus intergenic consensus sequence.
The ability of cyclodextrins to enhance the antiviral activity of a phosphodiester oligodeoxynucleotide has been investigated. A 18-mer oligodeoxynucleotide complementary to the initiation region of the mRNA coding for the spike protein and containing the intergenic consensus sequence of an enteric coronavirus has been tested for antiviral action against virus growth in human adenocarcinoma cells. The phosphodiester oligodeoxynucleotide only showed a limited effect on virus growth rate (from 12 to 34% viral inhibition in cells treated with 7.5 to 25 microM oligodeoxynucleotide, respectively, at a multiplicity of infection of 0.1 infectious particle per cell). In the same conditions, the phosphorothioate analogue exhibited stronger antiviral activity, the inhibition increased from 56 to 90%. The inhibitory effect of this analogue was antisense and sequence-specific. Northern blot analysis showed that the sequence-dependent mechanism of action appears to be the inhibition of mRNA transcription. We conclude that the coronavirus intergenic consensus sequence is a good target for an antisense oligonucleotide antiviral action. The properties of the phosphodiester oligonucleotide was improved after its complexation with cyclodextrins. The most important increase of the antiviral activity (90% inhibition) was obtained with only 7.5 microM oligonucleotide complexed to a cyclodextrin derivative, 6-deoxy-6-S-beta-D-galactopyranosyl-6-thio-cyclomalto-heptaose+ ++ in a molar ratio of 1:100. These studies suggest that the use of cyclodextrin derivatives as carrier for phosphodiester oligonucleotides delivery may be an effective method for increasing the therapeutic potential of these compounds in viral infections.
GEVSM, EA 1123, Université Henri Poincaré, Faculté de Pharmacie, Nancy, France.
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D002478:Cells, Cultured / Q000187:drug effects; D016384:Consensus Sequence / Q000187:drug effects*; D017934:Coronavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D003505:Cyclodextrins / Q000494:pharmacology; D004337:Drug Carriers; D007438:Introns / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D004337:Drug Carriers; D016376:Oligonucleotides, Antisense; D012367:RNA, Viral; D047392:beta-Cyclodextrins; C031215:betadex