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Journal of Virology, June 2004, p. 5891-5899, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5891-5899.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antisense Morpholino-Oligomers Directed against the 5' End of the Genome Inhibit Coronavirus Proliferation and Growth{dagger}

Benjamin W. Neuman,1* David A. Stein,2 Andrew D. Kroeker,2 Amy D. Paulino,1 Hong M. Moulton,2 Patrick L. Iversen,2 and Michael J. Buchmeier1

The Scripps Research Institute, Department of Neuropharmacology, Division of Virology, La Jolla, California 92037,1 AVI BioPharma, Corvallis, Oregon 973332

Received 17 September 2003/ Accepted 27 January 2004

Conjugation of a peptide related to the human immunodeficiency virus type 1 Tat represents a novel method for delivery of antisense morpholino-oligomers. Conjugated and unconjugated oligomers were tested to determine sequence-specific antiviral efficacy against a member of the Coronaviridae, Mouse hepatitis virus (MHV). Specific antisense activity designed to block translation of the viral replicase polyprotein was first confirmed by reduction of luciferase expression from a target sequence-containing reporter construct in both cell-free and transfected cell culture assays. Peptide-conjugated morpholino-oligomers exhibited low toxicity in DBT astrocytoma cells used for culturing MHV. Oligomer administered at micromolar concentrations was delivered to >80% of cells and inhibited virus titers 10- to 100-fold in a sequence-specific and dose-responsive manner. In addition, targeted viral protein synthesis, plaque diameter, and cytopathic effect were significantly reduced. Inhibition of virus infectivity by peptide-conjugated morpholino was comparable to the antiviral activity of the aminoglycoside hygromycin B used at a concentration fivefold higher than the oligomer. These results suggest that this composition of antisense compound has therapeutic potential for control of coronavirus infection.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Neuropharmacology, Division of Virology, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-7162. Fax: (858) 784-7369. E-mail: bneuman{at}scripps.edu. {dagger} TSRI paper no. 16375-NP.

Journal of Virology, June 2004, p. 5891-5899, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5891-5899.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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