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|Title:||Inhibition of multiple subtypes of influenza A virus in cell cultures with morpholino oligomers|
Richard K. Bestwick
Patrick L. Iversen
David A. Stein
Massachusetts Institute of Technology
Oregon State University
Agence de la sante publique du Canada
AVI BioPharma Incorporated
|Keywords:||Medicine;Pharmacology, Toxicology and Pharmaceutics|
|Citation:||Antimicrobial Agents and Chemotherapy. Vol.50, No.11 (2006), 3724-3733|
|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. Copyright © 2006, American Society for Microbiology. All Rights Reserved.|
|Appears in Collections:||Scopus 2006-2010|
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