Unique Small Molecule Entry Inhibitors of Hemorrhagic Fever Arenaviruses

Lee, Andrew M.; Rojek, Jillian M.; Spiropoulou, Christina F.; Gundersen, Anette; Jin, Wei; Shaginian, Alex; York, Joanne; Nunberg, Jack H.; Boger, Dale L.; Oldstone, Michael B. A.; Kunz, Stefan

doi:10.1074/jbc.m802089200

Cited by 88 publications

(104 citation statements)

References 40 publications

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“…F3406 differs chemically from several distinct classes of compounds that have been previously shown to inhibit arenavirus GPC-mediated membrane fusion by binding to a common site on GPC and stabilizing the prefusion GPC complex (39,(42)(43)(44)(45). Interestingly, previous work by Larson et al showed that arenavirus sensitivity or resistance to the cell entry inhibitor ST-193 correlated with the presence of V or M residues, respectively, at a GP2 position corresponding to M437 in LCMV (43).…”

Section: Discussionmentioning

confidence: 99%

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Ngo

Cubitt

Iwasaki

et al. 2015

J Virol

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Several arenaviruses cause hemorrhagic fever disease in humans and represent important public health problems in the regions where these viruses are endemic. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is an important neglected human pathogen. There are no licensed arenavirus vaccines and current antiarenavirus therapy is limited to the use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel antiarenaviral therapeutics. Here, we report the generation of a novel recombinant LCM virus and its use to develop a cell-based high-throughput screen to rapidly identify inhibitors of LCMV multiplication. We used this novel assay to screen a library of 30,400 small molecules and identified compound F3406 ( A renaviruses are enveloped viruses with a bisegmented negative-strand RNA genome. Each genome segment, large (L; ϳ7.3 kb) and small (S; ϳ3.5 kb) uses an ambisense coding strategy to direct synthesis of two polypeptides in opposite direction, separated by a noncoding intergenic region (IGR) (1, 2). The S segment encodes for the viral nucleoprotein (NP) and the glycoprotein precursor (GPC), which is co-and posttranslationally processed by the signal peptidase and SKI-1/S1P cellular proteases, respectively, to produce the mature surface virion glycoproteins GP1 and GP2 and the stable signal peptide (SSP) that together form the GP1/GP2/SSP complex present at the surface of mature virions and that mediate receptor recognition and cell entry (1, 3). The L segment encodes the viral RNA-dependent RNA polymerase (L polymerase) and the matrix Z protein. Arenaviruses cause chronic infections of rodents with worldwide distribution, where human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious material. Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose important public health problems in regions where these viruses are endemic (1, 4-8). Thus, Lassa virus (LASV) infects several hundred thousand people yearly in West Africa, resulting in a high number of Lassa fever cases that are associated with high morbidity and mortality. Likewise, Junin virus (JUNV) causes Argentine HF, a severe illness endemic to Pampas in Argentina, which is characterized by hemorrhagic and neurological manifestations and a fatality rate of 15 to 30% (8). Moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance (9-12). In addition, several arenaviruses, including LASV, JUNV, and LCMV, pose a credible biodefense threat (13). Concerns about arenavirus infections of humans are exacerbated due to the lack of U.S. Food and Drug Administrationlicensed vaccines and current antiarenaviral therapy being limited to an off-label use of ribavirin (Rib) that is only partially effective (14-16). Therefore, there is an unmet need to iden...

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Section: Discussionmentioning

confidence: 99%

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Ngo

Cubitt

Iwasaki

et al. 2015

J Virol

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“…Recently, we and others have identified novel classes of arenavirus entry inhibitors, including DNA aptamers (19) and several potent small-molecule inhibitors (3,20). While such entry inhibitors are likely efficacious early in infection, they are rather ineffective once the host cell has become infected.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Proteolytic Processing of the Viral Glycoprotein Precursor Is a Promising Novel Antiviral Strategy against Arenaviruses

Rojek

Pasqual

Sánchez

et al. 2010

J Virol

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A crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (GP) responsible for virus attachment and entry. Processing of the GP precursor (GPC) by the cellular proprotein convertase site 1 protease (S1P), also known as subtilisin-kexin-isozyme 1 (SKI-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. Here, we sought to evaluate arenavirus GPC processing by S1P as a target for antiviral therapy using a recently developed peptide-based S1P inhibitor, decanoyl (dec)-RRLL-chloromethylketone (CMK), and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). To control for off-target effects of dec-RRLL-CMK, we employed arenavirus reverse genetics to introduce a furin recognition site into the GPC of LCMV. The rescued mutant virus grew to normal titers, and the processing of its GPC critically depended on cellular furin, but not S1P.

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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.…”

mentioning

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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Unique Small Molecule Entry Inhibitors of Hemorrhagic Fever Arenaviruses

Abstract: Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and

Cited by 88 publications

References 40 publications

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Targeting the Proteolytic Processing of the Viral Glycoprotein Precursor Is a Promising Novel Antiviral Strategy against Arenaviruses

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

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