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Journal of Virology, November 2008, p. 10768-10775, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00941-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of a Broad-Spectrum Arenavirus Entry Inhibitor{triangledown}

Ryan A. Larson, Dongcheng Dai, Virginia T. Hosack, Ying Tan, Tove’ C. Bolken, Dennis E. Hruby, and Sean M. Amberg*

SIGA Technologies, Inc., Corvallis, Oregon 97333

Received 6 May 2008/ Accepted 12 August 2008

Several arenaviruses, including Lassa virus (LASV), are causative agents of hemorrhagic fever, for which effective therapeutic options are lacking. The LASV envelope glycoprotein (GP) gene was used to generate lentiviral pseudotypes to identify small-molecule inhibitors of viral entry. A benzimidazole derivative with potent antiviral activity was identified from a high-throughput screen utilizing this strategy. Subsequent lead optimization for antiviral activity identified a modified structure, ST-193, with a 50% inhibitory concentration (IC50) of 1.6 nM against LASV pseudotypes. ST-193 inhibited pseudotypes generated with other arenavirus envelopes as well, including the remaining four commonly associated with hemorrhagic fever (IC50s for Junín, Machupo, Guanarito, and Sabiá were in the 0.2 to 12 nM range) but exhibited no antiviral activity against pseudotypes incorporating either the GP from the LASV-related arenavirus lymphocytic choriomeningitis virus (LCMV) or the unrelated G protein from vesicular stomatitis virus, at concentrations of up to 10 µM. Determinants of ST-193 sensitivity were mapped through a combination of LASV-LCMV domain-swapping experiments, genetic selection of viral variants, and site-directed mutagenesis. Taken together, these studies demonstrate that sensitivity to ST-193 is dictated by a segment of about 30 amino acids within the GP2 subunit. This region includes the carboxy-terminal region of the ectodomain and the predicted transmembrane domain of the envelope protein, revealing a novel antiviral target within the arenavirus envelope GP.

* Corresponding author. Mailing address: 4575 SW Research Way, Suite 230, Corvallis, OR 97333. Phone: (541) 753-2000. Fax: (541) 753-9999. E-mail: SAmberg{at}siga.com

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, November 2008, p. 10768-10775, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00941-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Agnihothram, S. S., Dancho, B., Grant, K. W., Grimes, M. L., Lyles, D. S., Nunberg, J. H. (2009). Assembly of Arenavirus Envelope Glycoprotein GPC in Detergent-Soluble Membrane Microdomains. J. Virol. 83: 9890-9900 [Abstract] [Full Text]  
  • York, J., Nunberg, J. H. (2009). Intersubunit Interactions Modulate pH-Induced Activation of Membrane Fusion by the Junin Virus Envelope Glycoprotein GPC. J. Virol. 83: 4121-4126 [Abstract] [Full Text]  
  • York, J., Dai, D., Amberg, S. M., Nunberg, J. H. (2008). pH-Induced Activation of Arenavirus Membrane Fusion Is Antagonized by Small-Molecule Inhibitors. J. Virol. 82: 10932-10939 [Abstract] [Full Text]  


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