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Inhibition of Coxsackievirus B3 in Cell Cultures and in Mice by Peptide-Conjugated Morpholino Oligomers Targeting the Internal Ribosome Entry Site

Ji Yuan,¹ David A. Stein,^2, Travis Lim,^1, Dexin Qiu,¹ Shaun Coughlin,¹ Zhen Liu,¹ Yinjing Wang,¹ Robert Blouch,² Hong M. Moulton,² Patrick L. Iversen,² and Decheng Yang^1*

The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada,¹ AVI BioPharma, Inc., Corvallis, Oregon²

Received 3 May 2006/ Accepted 4 September 2006

Coxsackievirus B3 (CVB3) is a primary cause of viral myocarditis, yet no effective therapeutic against CVB3 is available. Nucleic acid-based interventional strategies against various viruses, including CVB3, have shown promise experimentally, but limited stability and inefficient delivery in vivo remain as obstacles to their potential as therapeutics. We employed phosphorodiamidate morpholino oligomers (PMO) conjugated to a cell-penetrating arginine-rich peptide, P007 (to form PPMO), to address these issues. Eight CVB3-specific PPMO were evaluated with HeLa cells and HL-1 cardiomyocytes in culture and in a murine infection model. One of the PPMO (PPMO-6), designed to target a sequence in the 3' portion of the CVB3 internal ribosomal entry site, was found to be especially potent against CVB3. Treatment of cells with PPMO-6 prior to CVB3 infection produced an approximately 3-log₁₀ decrease in viral titer and largely protected cells from a virus-induced cytopathic effect. A similar antiviral effect was observed when PPMO-6 treatment began shortly after the virus infection period. A/J mice receiving intravenous administration of PPMO-6 once prior to and once after CVB3 infection showed an 2-log₁₀-decreased viral titer in the myocardium at 7 days postinfection and a significantly decreased level of cardiac tissue damage, compared to the controls. Thus, PPMO-6 provided potent inhibition of CVB3 amplification both in cell cultures and in vivo and appears worthy of further evaluation as a candidate for clinical development.

Published ahead of print on 20 September 2006.

Both authors contributed equally to this work as second authors.

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