Combination Therapy for Hepatitis C Virus with Heat-Shock Protein 90 Inhibitor 17-AAG and Proteasome Inhibitor MG132

Ujino, Saneyuki; Yamaguchi, Saori; Shimotohno, Kunitada; Takaku, Hiroshi

doi:10.3851/imp1479

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…A study about hepatitis E virus (HEV) shows that the inhibitory role of high concentration of MG132 in viral replication was nonspecific considering the role of MG132 in widespread depression of expression of cellular proteins (Xu et al, 2015). It has been identified that MG132 at an even lower concentration of 5 nM could suppress HCV RNA replication by 85% without any influence on cell viability (Ujino et al, 2010). In this study, MG132 of high concentrations decreased CSFV replication and increased expressions of ISGs at the same time (Figure 4), indicating that the impact of MG132 on CSFV replication is specific.…”

Section: Discussionmentioning

confidence: 99%

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Chen

Fan

et al. 2020

Front. Microbiol.

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The 26S proteasome, in charge of intracellular protein degradation, plays significant roles in the modulation of various cellular activities as well as in the interplay between virus and host. However, studies about the relationship between 26S proteasome and classical swine fever virus (CSFV) is limited up to now. MG132 is a proteasome inhibitor and has been extensively used in studies about replication of many viruses. Herein, we investigated the role of MG132 in CSFV replication and results showed that MG132 significantly decreased virus titers and viral RNA copies in CSFV-infected PK-15 cells. Further studies demonstrated that MG132 upregulated the expression of several interferon-stimulated genes (ISGs), in CSFV-infected cells. Since the activation of ISGs is controlled by the JAK-STAT signal pathway, we next examined the effect of MG132 on the expression and localization of key molecular STAT1 in the infected cells using Western blot and confocal laser scanning microscopy, respectively. Results showed that CSFV infection and viral NS4A protein decreased the protein level of STAT1, and MG132 promoted the accumulation of STAT1 in the nucleus of cells adjacent to the CSFVinfected cells. Besides, MG132 did not affect the expressions of IFN-α, STAT1, Mx1, OAS1, and PKR genes in cells without CSFV. In conclusion, we identify that MG132 significantly inhibits CSFV replication in vitro, in which the activation of the JAK-STAT pathway and the subsequent upregulation of expressions of ISGs might play significant roles, providing a potential preventive method for CSF.

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Section: Discussionmentioning

confidence: 99%

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Chen

Fan

et al. 2020

Front. Microbiol.

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“…However, targeting host factors required for RNA virus propagation could be an attractive approach for developing antivirals with broad and durable activity. For example, pharmacological inhibition of hsp90 impaired the replication of HCV, (88) poliovirus, rhinovirus, and coxsackievirus in cell culture and in infected animals. (89) Importantly, anti-Hsp90 treatment did not lead to the emergence of drug-resistant escape mutant viruses.…”

Section: Roles Of Molecular Chaperones In Viral Rna Replicationmentioning

confidence: 99%

Host factors in the replication of positive-strand RNA viruses

Wang¹,

Li²

2012

Biomed J

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Viruses are obligate, intracellular parasites that depend on host cells for successful propagation. Upon infection of host cells, positivestrand RNA viruses exploit and hijack cellular machinery and reprogram these cells into viral "factories" through various protein-protein, protein-RNA, and protein-lipid interactions. The molecular interplay between host factors and invading viruses is a continuous process throughout the entire viral life cycle and determines virus host range and viral pathogenesis, as well as driving viral evolution. Studies of host factors have contributed insights into their normal cellular functions and helped identify attractive targets for antiviral drug development. With the development of high throughput screening, functional genomics, and proteomics technologies, host factors participating in viral life cycles have been identified rapidly in recent years. In this review, we summarize the recent advances in virus-host cell interactions in positive-strand RNA virus infections and focus on host factors that facilitate viral replication.

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“…The cyclosporin A-analog Debio-025, which inhibits CypA, reduced viral load in combination with pegylyated interferon-α and ribavirin, without the emergence of viral resistance and has been generally well-tolerated [4]. 17-(Allylamino)-17-demethoxygeldanamycin, (17-AAG), an HSP90 inhibitor, showed potent pre-clinical efficacy against a number of viral targets including hepatitis C [6], [7], ebola [8], hepatitis B [9], [10],and influenza [11]. Drug-resistance is suppressed by HSP90 inhibitors in polio-infected mice [3].…”

Section: Introductionmentioning

confidence: 99%

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

et al. 2012

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During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

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Combination Therapy for Hepatitis C Virus with Heat-Shock Protein 90 Inhibitor 17-AAG and Proteasome Inhibitor MG132

Abstract: Background: Hepatitis C virus (HCV) infection is a major

Cited by 5 publications

References 33 publications

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

MG132 Attenuates the Replication of Classical Swine Fever Virus in vitro

Host factors in the replication of positive-strand RNA viruses

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

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