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 Yang, G.
Right arrow Articles by Jordan, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, G.
Right arrow Articles by Jordan, R.

 Previous Article  |  Next Article 

Journal of Virology, October 2005, p. 13139-13149, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.13139-13149.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge

Guang Yang,5 Daniel C. Pevear,1,{dagger} Marc H. Davies,1,{ddagger} Marc S. Collett,1,§ Tom Bailey,1,¶ Susan Rippen,1,|| Linda Barone,1,# Chris Burns,1,{dagger}{dagger} Gerry Rhodes,1 Sanjeev Tohan,1,{ddagger}{ddagger} John W. Huggins,3 Robert O. Baker,3,§§ R. L. Mark Buller,2 Erin Touchette,2 Kem Waller,2 Jill Schriewer,2 Johan Neyts,4 Erik DeClercq,4 Kevin Jones,5 Dennis Hruby,5 and Robert Jordan5*

ViroPharma, Inc., Exton, Pennsylvania,1 Saint Louis University, St. Louis, Missouri,2 United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland,3 Rega Institute for Medical Research KULeuven, Leuven, Belgium,4 SIGA Technologies, Inc., Corvallis, Oregon5

Received 12 May 2005/ Accepted 14 July 2005

ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 µM), selective (concentration of compound that inhibited cell viability by 50% = >40 µM), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10x 50% lethal dose (LD50) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10x LD50) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40,000x LD50 of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2 x 107, 5.2 x 107, and 1.8 x 105 PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease.

* Corresponding author. Mailing address: SIGA Technologies, Inc., Corvallis, Oreg. Phone: (541) 753-2000. Fax: (541) 753-9999. E-mail: rjordan{at}sgph.com.

{dagger} Present address: Progenics Pharmaceuticals, Inc., Tarrytown, NY.

{ddagger} Present address: Bristol Myers Squibb Company, Princeton, NJ.

§ Present address: ViroDefense, Inc., Washington, DC.

Present address: Cephalon, Inc., West Chester, PA.

|| Present address: Gentera, Inc., Malvern, PA.

# Present address: AstraZeneca, Wilmington, DE.

{dagger}{dagger} Present address: Protez, Inc., Malvern, PA.

{ddagger}{ddagger} Present address: Exelixis, Inc., San Francisco, CA.

§§ Present address: American Type Culture Collection, Manassas, VA.

Journal of Virology, October 2005, p. 13139-13149, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.13139-13149.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Berhanu, A., King, D. S., Mosier, S., Jordan, R., Jones, K. F., Hruby, D. E., Grosenbach, D. W. (2009). ST-246 Inhibits In Vivo Poxvirus Dissemination, Virus Shedding, and Systemic Disease Manifestation. Antimicrob. Agents Chemother. 53: 4999-5009 [Abstract] [Full Text]  
  • Vigne, S., Duraffour, S., Andrei, G., Snoeck, R., Garin, D., Crance, J.-M. (2009). Inhibition of Vaccinia Virus Replication by Two Small Interfering RNAs Targeting B1R and G7L Genes and Their Synergistic Combination with Cidofovir. Antimicrob. Agents Chemother. 53: 2579-2588 [Abstract] [Full Text]  
  • Huggins, J., Goff, A., Hensley, L., Mucker, E., Shamblin, J., Wlazlowski, C., Johnson, W., Chapman, J., Larsen, T., Twenhafel, N., Karem, K., Damon, I. K., Byrd, C. M., Bolken, T. C., Jordan, R., Hruby, D. (2009). Nonhuman Primates Are Protected from Smallpox Virus or Monkeypox Virus Challenges by the Antiviral Drug ST-246. Antimicrob. Agents Chemother. 53: 2620-2625 [Abstract] [Full Text]  
  • Jordan, R., Goff, A., Frimm, A., Corrado, M. L., Hensley, L. E., Byrd, C. M., Mucker, E., Shamblin, J., Bolken, T. C., Wlazlowski, C., Johnson, W., Chapman, J., Twenhafel, N., Tyavanagimatt, S., Amantana, A., Chinsangaram, J., Hruby, D. E., Huggins, J. (2009). ST-246 Antiviral Efficacy in a Nonhuman Primate Monkeypox Model: Determination of the Minimal Effective Dose and Human Dose Justification. Antimicrob. Agents Chemother. 53: 1817-1822 [Abstract] [Full Text]  
  • Smith, S. K., Olson, V. A., Karem, K. L., Jordan, R., Hruby, D. E., Damon, I. K. (2009). In Vitro Efficacy of ST246 against Smallpox and Monkeypox. Antimicrob. Agents Chemother. 53: 1007-1012 [Abstract] [Full Text]  
  • Kern, E. R., Prichard, M. N., Quenelle, D. C., Keith, K. A., Tiwari, K. N., Maddry, J. A., Secrist, J. A. III (2009). Activities of Certain 5-Substituted 4'-Thiopyrimidine Nucleosides against Orthopoxvirus Infections. Antimicrob. Agents Chemother. 53: 572-579 [Abstract] [Full Text]  
  • Ahmed, C. M., Dabelic, R., Waiboci, L. W., Jager, L. D., Heron, L. L., Johnson, H. M. (2009). SOCS-1 Mimetics Protect Mice against Lethal Poxvirus Infection: Identification of a Novel Endogenous Antiviral System. J. Virol. 83: 1402-1415 [Abstract] [Full Text]  
  • Wei, H., Huang, D., Fortman, J., Wang, R., Shao, L., Chen, Z. W. (2009). Coadministration of Cidofovir and Smallpox Vaccine Reduced Vaccination Side Effects but Interfered with Vaccine-Elicited Immune Responses and Immunity to Monkeypox. J. Virol. 83: 1115-1125 [Abstract] [Full Text]  
  • McSharry, J. J., Deziel, M. R., Zager, K., Weng, Q., Drusano, G. L. (2009). Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an In Vitro Hollow-Fiber Infection Model System. Antimicrob. Agents Chemother. 53: 129-135 [Abstract] [Full Text]  
  • Gammon, D. B., Snoeck, R., Fiten, P., Krecmerova, M., Holy, A., De Clercq, E., Opdenakker, G., Evans, D. H., Andrei, G. (2008). Mechanism of Antiviral Drug Resistance of Vaccinia Virus: Identification of Residues in the Viral DNA Polymerase Conferring Differential Resistance to Antipoxvirus Drugs. J. Virol. 82: 12520-12534 [Abstract] [Full Text]  
  • Caillat, C., Topalis, D., Agrofoglio, L. A., Pochet, S., Balzarini, J., Deville-Bonne, D., Meyer, P. (2008). Crystal structure of poxvirus thymidylate kinase: An unexpected dimerization has implications for antiviral therapy. Proc. Natl. Acad. Sci. USA 105: 16900-16905 [Abstract] [Full Text]  
  • Yoon, J.-J., Chawla, D., Paal, T., Ndungu, M., Du, Y., Kurtkaya, S., Sun, A., Snyder, J. P., Plemper, R. K. (2008). High-Throughput Screening--Based Identification of Paramyxovirus Inhibitors. J Biomol Screen 13: 591-608 [Abstract]  
  • Jordan, R., Tien, D., Bolken, T. C., Jones, K. F., Tyavanagimatt, S. R., Strasser, J., Frimm, A., Corrado, M. L., Strome, P. G., Hruby, D. E. (2008). Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor. Antimicrob. Agents Chemother. 52: 1721-1727 [Abstract] [Full Text]  
  • Deng, L., Dai, P., Ciro, A., Smee, D. F., Djaballah, H., Shuman, S. (2007). Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly. J. Virol. 81: 13392-13402 [Abstract] [Full Text]  
  • Quenelle, D. C., Prichard, M. N., Keith, K. A., Hruby, D. E., Jordan, R., Painter, G. R., Robertson, A., Kern, E. R. (2007). Synergistic Efficacy of the Combination of ST-246 with CMX001 against Orthopoxviruses. Antimicrob. Agents Chemother. 51: 4118-4124 [Abstract] [Full Text]  
  • Quenelle, D. C., Collins, D. J., Herrod, B. P., Keith, K. A., Trahan, J., Beadle, J. R., Hostetler, K. Y., Kern, E. R. (2007). Effect of Oral Treatment with Hexadecyloxypropyl-[(S)-9-(3-Hydroxy-2- Phosphonylmethoxypropyl)Adenine] [(S)-HPMPA] or Octadecyloxyethyl-(S)-HPMPA on Cowpox or Vaccinia Virus Infections in Mice. Antimicrob. Agents Chemother. 51: 3940-3947 [Abstract] [Full Text]  
  • Prichard, M. N., Keith, K. A., Johnson, M. P., Harden, E. A., McBrayer, A., Luo, M., Qiu, S., Chattopadhyay, D., Fan, X., Torrence, P. F., Kern, E. R. (2007). Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase. Antimicrob. Agents Chemother. 51: 1795-1803 [Abstract] [Full Text]  
  • SBRANA, E., JORDAN, R., HRUBY, D. E., MATEO, R. I., XIAO, S.-Y., SIIRIN, M., NEWMAN, P. C., DA ROSA, A. P. A. T., TESH, R. B. (2007). EFFICACY OF THE ANTIPOXVIRUS COMPOUND ST-246 FOR TREATMENT OF SEVERE ORTHOPOXVIRUS INFECTION. Am J Trop Med Hyg 76: 768-773 [Abstract] [Full Text]  
  • Quenelle, D. C., Buller, R. M. L., Parker, S., Keith, K. A., Hruby, D. E., Jordan, R., Kern, E. R. (2007). Efficacy of Delayed Treatment with ST-246 Given Orally against Systemic Orthopoxvirus Infections in Mice. Antimicrob. Agents Chemother. 51: 689-695 [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»