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Inhibition of multiple subtypes of influenza A virus in cell cultures with morpholino oligomers.
|Title||Inhibition of multiple subtypes of influenza A virus in cell cultures with morpholino oligomers.|
|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Ge Q, Pastey M, Kobasa D, Puthavathana P, Lupfer C, Bestwick RK, Iversen PL, Chen J, Stein DA|
|Journal||Antimicrobial agents and chemotherapy|
|Date Published||2006 Nov|
|Keywords||Animals, Antiviral Agents, Cell Survival, Cells, Cultured, Cercopithecus aethiops, Cytopathogenic Effect, Viral, Dose-Response Relationship, Drug, Drug Design, Hemagglutination Tests, Humans, Influenza A virus, Morpholines, Protein Biosynthesis, RNA, Messenger, RNA, Viral, Vero Cells, Viral Plaque Assay|
Peptide-conjugated phosphorodiamidate morpholino oligomers (P-PMO) are single-stranded nucleic acid-like antisense agents that can reduce gene expression by sterically blocking complementary RNA sequence. P-PMO are water soluble and nuclease resistant, and they readily achieve uptake into cells in culture under standard conditions. Eight P-PMO, each 20 to 22 bases in length, were evaluated for their ability to inhibit influenza A virus (FLUAV) A/PR/8/34 (H1N1) replication in cell culture. The P-PMO were designed to base pair with FLUAV RNA sequences that are highly conserved across viral subtypes and considered critical to the FLUAV biological-cycle, such as gene segment termini and mRNA translation start site regions. Several P-PMO were highly efficacious, each reducing viral titer in a dose-responsive and sequence-specific manner in A/PR/8/34-infected cells. Two P-PMO, one designed to target the AUG translation start site region of PB1 mRNA and the other the 3'-terminal region of nucleoprotein viral genome RNA, also proved to be potent against several other FLUAV strains, including A/WSN/33 (H1N1), A/Memphis/8/88 (H3N2), A/Eq/Miami/63 (H3N8), A/Eq/Prague/56 (H7N7), and the highly pathogenic A/Thailand/1(KAN-1)/04 (H5N1). The P-PMO exhibited minimal cytotoxicity in cell viability assays. High efficacy by two of the P-PMO against multiple FLUAV subtypes suggests that these oligomers represent a broad-spectrum therapeutic approach against a high percentage of known FLUAV strains.
|Alternate Journal||Antimicrob. Agents Chemother.|