Screening and identification of compounds with antiviral activity against hepatitis B virus using a safe compound library and novel real-time immune-absorbance PCR-based high throughput system

Lamontagne, Jason; Mills, Courtney; Mao, Richeng; Goddard, Cally; Guo, Haitao; Cuconati, Andy; Block, Timothy M.; Lu, Xuanyong

doi:10.1016/j.antiviral.2013.02.001

Cited by 14 publications

(12 citation statements)

References 33 publications

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“…Cultured primary rat hepatocytes were infected with AdHBV and then treated with LY294002 or the vehicle control. Primary rat hepatocyte cell culture medium supernatants were collected 48 h after treatment, and enveloped HBV particles were captured by using an anti-HBs antibody as previously described (55). The captured HBV particles were then subjected to real-time PCR with HBV-specific primers to quantify the levels of enveloped HBV particles in the supernatant.…”

Section: Resultsmentioning

confidence: 99%

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The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

113

126

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Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4␣ (HNF4␣) is a target of HBx-regulated AKT, and we link HNF4␣ to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is Chronic infection with hepatitis B virus (HBV) remains a major global health problem. Despite the availability of effective HBV vaccines, there are ϳ350 million people worldwide who are chronically infected with HBV. Chronic HBV infection is the major cause of the development of hepatocellular carcinoma (HCC) (1). The level of HBV replication in a chronically HBV-infected individual can vary throughout the course of the infection, and the rise and fall of HBV replication during a chronic infection may affect disease progression (2, 3). There are limited therapeutic options for treating a chronic HBV infection, and the emergence of HBV mutants that are resistant to available therapies is common. Moreover, available anti-HBV drugs typically do not completely eliminate HBV in chronically infected individuals due to the presence and stability of covalently closed circular DNA (cccDNA), a replicative intermediate of HBV that is localized to the nucleus of HBV-infected hepatocytes (4-7). Consequently, there is continued interest in understanding the mechanisms that regulate HBV replication and could serve as potential therapeutic targets.HBV is an enveloped, partially double-stranded DNA virus that belongs to the Hepadnaviridae family of viruses (8). Although HBV is a DNA virus, it replicates through reverse transcription of an RNA intermediate. HBV replication occurs within the viral capsid in the cytosol of hepa...

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Section: Resultsmentioning

confidence: 99%

“…Enveloped HBV particles were captured, and quantitative real-time PCR (qRT-PCR) was performed as previously described (55). Briefly, 96-well plates were coated overnight with 250 ng of HBsAg antibody at 4°C, and the plate was then washed three times with TBST.…”

mentioning

confidence: 99%

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

113

126

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“…Raloxifene has been found to have an in vitro antiviral activity, in terms of inhibition of viral replication and/or infection, against EBOV [ 54 , 76 , 77 ], HCV [ 78 , 79 ], HBV [ 80 ], and Zika virus [ 81 ]. Further, it showed efficacy in human female cells from nasal epithelium, against the influenza virus A [ 82 ].…”

Section: Raloxifene: a Promising Serm For The Treatment Of Sars-cov2 Infectionmentioning

confidence: 99%

Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection

et al. 2021

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The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.

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“…SOSA provides an attractive strategy, by which new potential pharmacological activity of an old approved drug may be identified. Although some new anti-malarial, antibacterial and antiviral drugs have been developed by SOSA [7][8][9][10]14,[21][22][23], there is rarely reports about screening and identifying anti-M.tb drugs through this approach. In the present study, we used SOSA approach to screen out a new anti-M. tb drug, PP.…”

Section: Discussionmentioning

confidence: 99%

“…The safety and pharmacokinetic properties of these old drugs have been well evaluated in humans and animals, so the new biological activities of these approved drugs can be more rapidly and easily applied in clinical practice than new drugs. SOSA has been used in the development of new anti-malarial, antibacterial and antiviral drugs [7][8][9][10][11]. In the present study, we used the SOSA approach to screen out a new anti-M. tb drug, pyrvinium pamoate (PP), a US Food and Drug Administration (FDA)-approved drug from the MicroSource (Gaylordsville, CT) library consisting of 1280 drugs and compounds.…”

Section: Introductionmentioning

confidence: 99%

Identification of pyrvinium pamoate as an anti-tuberculosis agent in vitro and in vivo by SOSA approach amongst known drugs

Guan

Liu

et al. 2020

Emerging Microbes & Infections

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) bacteria, is a leading infectious cause of mortality worldwide. The emergence of drug-resistant M. tb has made control of TB more difficult. The selective optimization of side activities (SOSA) approach uses old drugs for new pharmacological targets. In the present study by using SOSA approach, we have successfully identified pyrvinium pamoate (PP) which is capable of inhibiting the growth of mycobacteria, including M. tb H37Rv, Mycobacterium smegmatis, Bacille Calmette-Guérin (BCG), M. tb H37Ra, and drugresistant M. tb clinical isolates in vitro from 1280 known drugs library. The MIC 99 of PP, the minimum inhibitory concentration that inhibits more than 99% of M. tb H37Rv and the drug-resistant M. tb clinical isolates, ranges from 1.55 to 4.8 µg/mL. Importantly, PP could reduce the bacterial colony-forming units (CFUs) in lung, spleen and liver tissues, and effectively inhibit inflammatory response in M. tb H37Rv, multidrug-resistant (MDR) M. tb and extensively drug-resistant (XDR) M.tb-infected mice. Our results clearly show that the PP has the potential application for treatment of TB.

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Screening and identification of compounds with antiviral activity against hepatitis B virus using a safe compound library and novel real-time immune-absorbance PCR-based high throughput system

Cited by 14 publications

References 33 publications

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection

Identification of pyrvinium pamoate as an anti-tuberculosis agent in vitro and in vivo by SOSA approach amongst known drugs

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