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 | Antimicrob Agents Chemother |
Volume | 50 |
Issue | 11 |
Pagination | 3724-33 |
Date Published | 2006 Nov |
ISSN | 0066-4804 |
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 |
Abstract | 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. |
DOI | 10.1128/AAC.00644-06 |
Alternate Journal | Antimicrob. Agents Chemother. |
PubMed ID | 16966399 |
PubMed Central ID | PMC1635187 |
Grant List | AI56267 / AI / NIAID NIH HHS / United States P50-CA112967 / CA / NCI NIH HHS / United States |