Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses

Bolken, Tove’ C.; Laquerre, Sylvie; Zhang, Yuanming; Bailey, T. R.; Pevear, Daniel C.; Kickner, Shirley S.; Sperzel, Lindsey; Jones, Kevin F.; Warren, Travis K.; Lund, Susan Amanda; Kirkwood-Watts, Dana L.; King, David S.; Shurtleff, Amy C.; Guttieri, Mary C.; Deng, Yunkun; Bleam, Maureen R.; Hruby, Dennis E.

doi:10.1016/j.antiviral.2005.10.008

Cited by 91 publications

(111 citation statements)

References 26 publications

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“…Studies had previously demonstrated that prior exposure of virions to ST-336 was sufficient to block subsequent infection of untreated cells (3). In order to determine the timing requirements for inhibition of cell-cell fusion, GPC-expressing cells were treated with 10 M ST-294 prior to the pH pulse, during the pH pulse, or upon return to neutrality (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

York

Dai

Amberg

et al. 2008

J Virol

159

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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 GPCmediated 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.

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Section: Resultsmentioning

confidence: 99%

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

York

Dai

Amberg

et al. 2008

J Virol

159

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“…Therefore, it is important to develop novel effective antiarenaviral drugs and vaccines, tasks that would be facilitated by a detailed understanding of the arenavirus molecular and cell biology. Recent studies have identified small molecule inhibitors of Tacaribe virus (7) and LASV (8) cell entry, but their antiviral activity in animal models of HF arenaviruses has not been examined.…”

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confidence: 99%

Generation of recombinant lymphocytic choriomeningitis viruses with trisegmented genomes stably expressing two additional genes of interest

Emonet

Garidou

McGavern

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

216

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Several arenaviruses cause hemorrhagic fever disease in humans for which no licensed vaccines are available and current therapeutic intervention is limited to the off-label use of the wide-spectrum antiviral ribavirin. However, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) has proven to be a Rosetta stone for the investigation of virus-host interactions. Arenaviruses have a bisegmented negative-strand RNA genome. The S segment encodes for the virus nucleoprotein and glycoprotein, whereas the L segment encodes for the virus polymerase (L) and Z protein. The ability to generate recombinant LCMV (rLCMV) expressing additional foreign genes of interest would open novel avenues for the study of virushost interactions and the development of novel vaccine strategies and high-throughput screens to identify antiarenaviral molecules. To this end, we have developed a trisegmented (1L ؉ 2S) rLCMV-based approach (r3LCMV). Each of the two S segments in r3LCMV was altered to replace one of the viral genes by a gene of interest. All r3LCMVs examined expressing different reported genes were stable both genetically and phenotypically and exhibited wild-type growth properties in cultured cells. Reporter gene expression in r3LCMV-infected cells provided an accurate surrogate of levels of virus multiplication. Notably, some r3LCMVs displayed highly attenuated virulence in mice but induced protective immunity against a subsequent lethal challenge with wild-type LCMV, supporting the potential development of r3LCMV-based vaccines.antiviral screen ͉ reverse genetic ͉ viral attenuation A renaviruses merit significant interest both as tractable experimental model systems to study acute and persistent viral infections and as clinically important human pathogens (1-3). Thus, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) has proven to be a superb workhorse in the field of virology and immunology (1). However, several arenaviruses cause hemorrhagic fever (HF) disease in humans, associated with high morbidity and mortality (2, 3). The Old World arenavirus Lassa virus (LASV) poses the highest public health concern among HF arenaviruses. LASV is estimated to infect several hundred thousand individuals yearly in its endemic region of West Africa, resulting in a high number of Lassa fever disease cases (2). Likewise, several New World arenaviruses, chiefly Junin virus, cause viral HF disease (3). Moreover, evidence indicates that the worldwide distributed LCMV is a neglected human pathogen of clinical significance (4) and poses a special threat to immunocompromised individuals (5, 6).Public health concerns posed by human pathogenic arenaviruses are aggravated by the lack of licensed vaccines and current therapy being limited to the use of the nucleoside analog ribavirin (Rib) that can cause significant side effects and requires an early and i.v. administration for optimal efficacy (3). Therefore, it is important to develop novel effective antiarenaviral drugs and vaccines, tasks that would be facilitated ...

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“…Intervention strategies that target the steps in virus entry offer promise for effective antiviral therapeutics. Indeed, small-molecule arenavirus-specific entry inhibitors have recently been discovered (5).…”

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confidence: 99%

A Novel Zinc-Binding Domain Is Essential for Formation of the Functional Junín Virus Envelope Glycoprotein Complex

York

Nunberg

2007

J Virol

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The envelope glycoprotein of the Junín arenavirus (GP-C) mediates entry into target cells through a pHdependent membrane fusion mechanism. Unlike other class I viral fusion proteins, the mature GP-C complex retains a cleaved, 58-amino-acid signal peptide (SSP) as an essential subunit, required both for trafficking of GP-C to the cell surface and for the activation of membrane fusion. SSP has been shown to associate noncovalently in GP-C via the cytoplasmic domain (CTD) of the transmembrane fusion subunit G2. In this report we investigate the molecular basis for this intersubunit interaction. We identify an invariant series of six cysteine and histidine residues in the CTD of G2 that is essential for incorporation of SSP in the GP-C complex. Moreover, we show that a CTD peptide fragment containing His-447, His-449, and Cys-455 specifically binds Zn 2؉ at subnanomolar concentrations. Together, these results suggest a zinc finger-like domain structure in the CTD of G2. We propose that the remaining residues in the series (His-459, Cys-467, and Cys-469) form an intersubunit zinc-binding center that incorporates Cys-57 of SSP. This unusual motif may act to retain SSP in the GP-C complex and position the ectodomain loop of SSP for its role in modulating membrane fusion activity. The unique tripartite organization of GP-C could provide novel molecular targets for therapeutic intervention in arenaviral disease.

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Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses

Cited by 91 publications

References 26 publications

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

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

Generation of recombinant lymphocytic choriomeningitis viruses with trisegmented genomes stably expressing two additional genes of interest

A Novel Zinc-Binding Domain Is Essential for Formation of the Functional Junín Virus Envelope Glycoprotein Complex

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