Selective inhibition of the cytopathic effect of type A influenza viruses by oligodeoxynucleotides covalently linked to an intercalating agent

Abstract

Oligodeoxynucleotides covalently linked to an acridine derivative were targeted to part of the 3'-terminal sequence which is common to the eight RNAs of type A influenza viruses. The cytopathic effect of the virus on MDCK cells in culture was strongly decreased by a heptanucleotide covalently attached to the acridine ring. Control experiments using other oligonucleotide sequences showed that the effect was specific for the complementary sequence of the 3'-terminal region of the viral RNAs. The RNA transcriptase reaction of a type A virus was also selectively inhibited in vitro by the heptanucleotide-acridine conjugate. A type B influenza virus was used as a control. The common sequence at the 3' end of its eight viral RNAs is different from that of type A viruses. Three mismatches were expected with the heptanucleotide which was fully complementary to type A viral RNAs. This heptanucleotide had no effect on the cytopathic effect of a type B influenza virus. These results demonstrate that viral RNAs are specific targets for the oligonucleotide-acridine conjugate that inhibits the cytopathic effect of type A influenza viruses.

Mechanisms of the inhibition of reverse transcription by unmodified and modified antisense oligonucleotides

“…Antisense oligonucleotides complementary to viral RNA inhibit viral replication in cells cultured with Rous sarcoma virus [7], human irnmunodeficiency virus [8-lo], vesicular stomatitis virus [11,12], herpes simplex virus [11,14], and influenza virus [14,15]. However, the mechanism by which the antisense oligonucleotide inhibited retroviral protein synthesis, syncytia formation, and reverse transcriptase activity has not been fully elucidated.…”

Cholesteryl-conjugated oligonucleotides: synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture.

“…The viruses studied in this context include Rous sarcoma virus (1), simian virus (5), vesicular stomatitis virus (6,13), human immunodeficiency virus (HIV) (8)(9)(10)(11)(12), herpes simplex virus (7), and influenza virus (14).…”

Blockage of AM V reverse transcriptase by antisense oligodeoxynucleotides

“…Acridinelinked oligonucleotides elicit RNase-H activity when bound to the complementary RNA sequence [20]. Moreover, it has been shown that such modified antisense oligomers can be used with intact cells, and prevent the development of the influenza virus [21] and of African trypanosomes in culture [14]. Our results indicate that they might also be of interest in the case of retroviruses.…”