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Journal of Virology, November 2008, p. 10932-10939, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01140-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

pH-Induced Activation of Arenavirus Membrane Fusion Is Antagonized by Small-Molecule Inhibitors{triangledown}

Joanne York,1 Dongcheng Dai,2 Sean M. Amberg,2 and Jack H. Nunberg1*

Montana Biotechnology Center, The University of Montana, Missoula, Montana 59812,1 SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, Oregon 973332

Received 30 May 2008/ Accepted 22 August 2008

The arenavirus envelope glycoprotein (GPC) mediates viral entry through pH-induced membrane fusion in the endosome. This crucial process in the viral life cycle can be specifically inhibited in the New World arenaviruses by the small-molecule compound ST-294. Here, we show that ST-294 interferes with GPC-mediated membrane fusion by targeting the interaction of the G2 fusion subunit with the stable signal peptide (SSP). We demonstrate that amino acid substitutions at lysine-33 of the Junín virus SSP confer resistance to ST-294 and engender de novo sensitivity to ST-161, a chemically distinct inhibitor of the Old World Lassa fever virus. These compounds, as well as a broadly active inhibitor, ST-193, likely share a molecular target at the SSP-G2 interface. We also show that both ST-294 and ST-193 inhibit pH-induced dissociation of the G1 receptor-binding subunit from GPC, a process concomitant with fusion activation. Interestingly, the inhibitory activity of these molecules can in some cases be overcome by further lowering the pH used for activation. Our results suggest that these small molecules act to stabilize the prefusion GPC complex against acidic pH. The pH-sensitive interaction between SSP and G2 in GPC represents a robust molecular target for the development of antiviral compounds for the treatment of arenavirus hemorrhagic fevers.

* Corresponding author. Mailing address: Montana Biotechnology Center, The University of Montana, Science Complex, Room 221, Missoula, MT 59812. Phone: (406) 243-6421. Fax: (406) 243-6425. E-mail: jack.nunberg{at}umontana.edu

{triangledown} Published ahead of print on 3 September 2008.

Journal of Virology, November 2008, p. 10932-10939, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01140-08
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]  
  • Larson, R. A., Dai, D., Hosack, V. T., Tan, Y., Bolken, T. C., Hruby, D. E., Amberg, S. M. (2008). Identification of a Broad-Spectrum Arenavirus Entry Inhibitor. J. Virol. 82: 10768-10775 [Abstract] [Full Text]  


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