Potent inhibition of respiratory syncytial virus replication using a 2-5A-antisense chimera targeted to signals within the virus genomic RNA.
The 2-5A system is a recognized mechanistic component of the antiviral action of interferon. Interferon-induced 2-5A synthetase generates 2-5A, which, in turn, activates the latent constitutive RNase L that degrades viral RNA. Chemical conjugation of 2-5A to an antisense oligonucleotide can target the 2-5A-dependent RNase L to the antisense-specified RNA and effect its selective destruction. Such a 2-5A-antisense chimera (NIH351) has been developed that targets a consensus sequence within the respiratory syncytial virus (RSV) genomic RNA. NIH351 was 50- to 90-fold more potent against RSV strain A2 than was ribavirin, the presently approved drug for clinical management of RSV infection. It was similarly active against a variety of RSV strains of both A and B subgroups and possessed a cell culture selectivity index comparable to ribavirin. In addition, the anti-RSV activity of NIH351 was shown to be virus-specific and a result of a true antisense effect, because a scrambled nucleotide sequence in the antisense domain of NIH351 caused a significant decrease in antiviral activity. The 2-5A system's RNase L was implicated in the mechanism of action of NIH351 because a congener with a disabled 2-5A moiety was of greatly reduced anti-RSV effectiveness. These findings represent an innovative approach to the control of RSV replication.
Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0805, USA.
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D000227:Adenine Nucleotides / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002678:Chimera; D002522:Chlorocebus aethiops; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000235:genetics*; D012367:RNA, Viral / Q000187:drug effects*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*
D000227:Adenine Nucleotides; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D012367:RNA, Viral; C023505:2',5'-oligoadenylate