This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Neuman, B. W.
Right arrow Articles by Buchmeier, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Neuman, B. W.
Right arrow Articles by Buchmeier, M. J.

 Previous Article  |  Next Article 

Journal of Virology, August 2005, p. 9665-9676, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9665-9676.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition, Escape, and Attenuated Growth of Severe Acute Respiratory Syndrome Coronavirus Treated with Antisense Morpholino Oligomers{dagger}

Benjamin W. Neuman,1* David A. Stein,4 Andrew D. Kroeker,4 Michael J. Churchill,2 Alice M. Kim,1 Peter Kuhn,2 Philip Dawson,2,3 Hong M. Moulton,4 Richard K. Bestwick,4 Patrick L. Iversen,4 and Michael J. Buchmeier1

The Scripps Research Institute, Division of Virology, Department of Neuropharmacology,1 Department of Cell Biology,2 Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Rd., La Jolla, California 92037,3 AVI BioPharma Inc., 4575 SW Research Way, Corvallis, Oregon 973334

Received 10 November 2004/ Accepted 4 April 2005

The recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV) is a potent pathogen of humans and is capable of rapid global spread. Peptide-conjugated antisense morpholino oligomers (P-PMO) were designed to bind by base pairing to specific sequences in the SARS-CoV (Tor2 strain) genome. The P-PMO were tested for their capacity to inhibit production of infectious virus as well as to probe the function of conserved viral RNA motifs and secondary structures. Several virus-targeted P-PMO and a random-sequence control P-PMO showed low inhibitory activity against SARS coronavirus. Certain other virus-targeted P-PMO reduced virus-induced cytopathology and cell-to-cell spread as a consequence of decreasing viral amplification. Active P-PMO were effective when administered at any time prior to peak viral synthesis and exerted sustained antiviral effects while present in culture medium. P-PMO showed low nonspecific inhibitory activity against translation of nontargeted RNA or growth of the arenavirus lymphocytic choriomeningitis virus. Two P-PMO targeting the viral transcription-regulatory sequence (TRS) region in the 5' untranslated region were the most effective inhibitors tested. After several viral passages in the presence of a TRS-targeted P-PMO, partially drug-resistant SARS-CoV mutants arose which contained three contiguous base point mutations at the binding site of a TRS-targeted P-PMO. Those partially resistant viruses grew more slowly and formed smaller plaques than wild-type SARS-CoV. These results suggest PMO compounds have powerful therapeutic and investigative potential toward coronavirus infection.

* Corresponding author. Mailing address: The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 858-784-7162. Fax: 858-784-7369. E-mail: bneuman{at}scripps.edu.

{dagger} This is TSRI manuscript 16974-NP.

Journal of Virology, August 2005, p. 9665-9676, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9665-9676.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Swenson, D. L., Warfield, K. L., Warren, T. K., Lovejoy, C., Hassinger, J. N., Ruthel, G., Blouch, R. E., Moulton, H. M., Weller, D. D., Iversen, P. L., Bavari, S. (2009). Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection. Antimicrob. Agents Chemother. 53: 2089-2099 [Abstract] [Full Text]  
  • Krahling, V., Stein, D. A., Spiegel, M., Weber, F., Muhlberger, E. (2009). Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity. J. Virol. 83: 2298-2309 [Abstract] [Full Text]  
  • Stone, J. K., Rijnbrand, R., Stein, D. A., Ma, Y., Yang, Y., Iversen, P. L., Andino, R. (2008). A Morpholino Oligomer Targeting Highly Conserved Internal Ribosome Entry Site Sequence Is Able To Inhibit Multiple Species of Picornavirus. Antimicrob. Agents Chemother. 52: 1970-1981 [Abstract] [Full Text]  
  • Vagnozzi, A., Stein, D. A., Iversen, P. L., Rieder, E. (2007). Inhibition of Foot-and-Mouth Disease Virus Infections in Cell Cultures with Antisense Morpholino Oligomers. J. Virol. 81: 11669-11680 [Abstract] [Full Text]  
  • Cheng, V. C. C., Lau, S. K. P., Woo, P. C. Y., Yuen, K. Y. (2007). Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection. Clin. Microbiol. Rev. 20: 660-694 [Abstract] [Full Text]  
  • Deas, T. S., Bennett, C. J., Jones, S. A., Tilgner, M., Ren, P., Behr, M. J., Stein, D. A., Iversen, P. L., Kramer, L. D., Bernard, K. A., Shi, P.-Y. (2007). In Vitro Resistance Selection and In Vivo Efficacy of Morpholino Oligomers against West Nile Virus. Antimicrob. Agents Chemother. 51: 2470-2482 [Abstract] [Full Text]  
  • Burrer, R., Neuman, B. W., Ting, J. P. C., Stein, D. A., Moulton, H. M., Iversen, P. L., Kuhn, P., Buchmeier, M. J. (2007). Antiviral Effects of Antisense Morpholino Oligomers in Murine Coronavirus Infection Models. J. Virol. 81: 5637-5648 [Abstract] [Full Text]  
  • Yuan, J., Stein, D. A., Lim, T., Qiu, D., Coughlin, S., Liu, Z., Wang, Y., Blouch, R., Moulton, H. M., Iversen, P. L., Yang, D. (2006). Inhibition of Coxsackievirus B3 in Cell Cultures and in Mice by Peptide-Conjugated Morpholino Oligomers Targeting the Internal Ribosome Entry Site. J. Virol. 80: 11510-11519 [Abstract] [Full Text]  
  • Ge, Q., Pastey, M., Kobasa, D., Puthavathana, P., Lupfer, C., Bestwick, R. K., Iversen, P. L., Chen, J., Stein, D. A. (2006). Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers. Antimicrob. Agents Chemother. 50: 3724-3733 [Abstract] [Full Text]  
  • Neuman, B. W., Adair, B. D., Yoshioka, C., Quispe, J. D., Orca, G., Kuhn, P., Milligan, R. A., Yeager, M., Buchmeier, M. J. (2006). Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy.. J. Virol. 80: 7918-7928 [Abstract] [Full Text]  
  • Enterlein, S., Warfield, K. L., Swenson, D. L., Stein, D. A., Smith, J. L., Gamble, C. S., Kroeker, A. D., Iversen, P. L., Bavari, S., Muhlberger, E. (2006). VP35 Knockdown Inhibits Ebola Virus Amplification and Protects against Lethal Infection in Mice. Antimicrob. Agents Chemother. 50: 984-993 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»