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Antimicrob. Agents Chemother. doi:10.1128/AAC.00644-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA. 02139, Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis Oregon 97331, Public Health Agency of Canada, Winnipeg, Manitoba, Canada, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, AVI BioPharma Inc., Corvallis, OR. 97333

^* To whom correspondence should be addressed. Email: steind{at}avibio.com.

	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, nuclease resistant, and readily achieve uptake into cells in culture under standard conditions. Eight P-PMO, each 20-22 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 basepair 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 NP vRNA, 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.

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