Hydroxamic Acids Block Replication of Hepatitis C Virus

Ai, Teng; Xü, Yanli; Qiu, Li; Geraghty, Robert J.; Chen, Liqiang

doi:10.1021/jm501330g

Cited by 39 publications

(17 citation statements)

References 51 publications

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“…Understanding the molecular mechanism underlying SAHA's inhibitory effects on HAdV may make it possible to design better compounds with longer-lasting effects and lower toxicity for the treatment of HAdV infections. As HDAC inhibitors have been reported to exhibit antiviral activity against other viruses, including respiratory syncytial virus and hepatitis C virus (69,80), these novel compounds may be useful in treating a variety of viral infections.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Saha

Parks

2019

J Virol

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Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease. IMPORTANCE Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Saha

Parks

2019

J Virol

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“…The broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and hydroxamic acids can inhibit HCV replication in vitro (Sato et al 2013;Ai et al 2015). These inhibitors target multiple HDACs including HDAC1, 2, and 3.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression

et al. 2018

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Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein a (C/EBPa), hypoxia-inducible factor 1a (HIF1a), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.

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“… 30 However, another study pointed toward significant cytotoxicity at a low molar concentration of SAHA treatment despite its anti-HCV activity. 117 Nevertheless, treatment with SAHA or the HDAC1/2/3 inhibitor CI994I or the HDAC3 inhibitor RGFP966 suppressed HCV replication in infected Huh7 cells, with no observed effect upon treatment with the HDAC8 inhibitor PCI-34051. Specifically, and consistent with the previously mentioned study, RGFP966 decreased the level of Apo-A1, which could suppress HCV assembly and secretion and increased the level of the liver-expressed antimicrobial peptide 1 (LEAP-1), which in turn could remit HCV infection and chronic liver injury.…”

Section: Cancer-inducing Virusesmentioning

confidence: 97%