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Journal of Virology, June 2007, p. 5637-5648, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02360-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiviral Effects of Antisense Morpholino Oligomers in Murine Coronavirus Infection Models{triangledown}

Renaud Burrer,1,{dagger} Benjamin W. Neuman,1,{ddagger} Joey P. C. Ting,1 David A. Stein,3 Hong M. Moulton,3 Patrick L. Iversen,3 Peter Kuhn,2 and Michael J. Buchmeier1*

Department of Molecular and Integrative Neurosciences,1 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037,2 AVI Biopharma Inc., 4575 SW Research Way, Corvallis, Oregon 973333

Received 27 October 2006/ Accepted 1 March 2007

The recent emergence of novel pathogenic human and animal coronaviruses has highlighted the need for antiviral therapies that are effective against a spectrum of these viruses. We have used several strains of murine hepatitis virus (MHV) in cell culture and in vivo in mouse models to investigate the antiviral characteristics of peptide-conjugated antisense phosphorodiamidate morpholino oligomers (P-PMOs). Ten P-PMOs directed against various target sites in the viral genome were tested in cell culture, and one of these (5TERM), which was complementary to the 5' terminus of the genomic RNA, was effective against six strains of MHV. Further studies were carried out with various arginine-rich peptides conjugated to the 5TERM PMO sequence in order to evaluate efficacy and toxicity and thereby select candidates for in vivo testing. In uninfected mice, prolonged P-PMO treatment did not result in weight loss or detectable histopathologic changes. 5TERM P-PMO treatment reduced viral titers in target organs and protected mice against virus-induced tissue damage. Prophylactic 5TERM P-PMO treatment decreased the amount of weight loss associated with infection under most experimental conditions. Treatment also prolonged survival in two lethal challenge models. In some cases of high-dose viral inoculation followed by delayed treatment, 5TERM P-PMO treatment was not protective and increased morbidity in the treated group, suggesting that P-PMO may cause toxic effects in diseased mice that were not apparent in the uninfected animals. However, the strong antiviral effect observed suggests that with further development, P-PMO may provide an effective therapeutic approach against a broad range of coronavirus infections.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Molecular and Integrative Neurosciences, Mail Drop SP30-2020, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-7164. Fax: (858) 784-7369. E-mail: buchm{at}scripps.edu

{triangledown} Published ahead of print on 7 March 2007.

{dagger} Present address: Centre d'Immunologie de Marseille-Luminy, Marseille, France.

{ddagger} Present address: University of Reading, Reading, Berkshire, United Kingdom.

Journal of Virology, June 2007, p. 5637-5648, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02360-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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