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J. Virol. doi:10.1128/JVI.01140-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

pH-INDUCED ACTIVATION OF ARENAVIRUS MEMBRANE FUSION IS ANTAGONIZED BY SMALL-MOLECULE INHIBITORS

Montana Biotechnology Center, The University of Montana, Missoula, MT 59812; SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, OR 97333

^* To whom correspondence should be addressed. Email: jack.nunberg{at}umontana.edu.

	Abstract

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. 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 pre-fusion 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.

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