A p7 Ion Channel-derived Peptide Inhibits Hepatitis C Virus Infection in Vitro

Hong, Wei; Lang, Yange; Tian, Li; Zeng, Zhengyang; Song, Yu; Wu, Yingliang; Li, Wenxin; Cao, Zhijian

doi:10.1074/jbc.m115.662452

Cited by 7 publications

(6 citation statements)

References 29 publications

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“…Recent advances in structure-activity relations have led to a better understanding of inhibitor binding, despite the variability of the structure and conformation of the p7 protein [10,[53][54][55][56][57]. An outlook for new therapeutic options may be the identification of a p7-derived peptide that was able to inhibit virus replication in vitro [58].…”

Section: Discussionmentioning

confidence: 99%

Cell viability assay as a tool to study activity and inhibition of hepatitis C p7 channels

Breitinger

Farag

Ali

et al. 2021

Journal of General Virology

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The p7 viroporin of the hepatitis C virus (HCV) forms an intracellular proton-conducting transmembrane channel in virus-infected cells, shunting the pH of intracellular compartments and thus helping virus assembly and release. This activity is essential for virus infectivity, making viroporins an attractive target for drug development. The protein sequence and drug sensitivity of p7 vary between the seven major genotypes of the hepatitis C virus, but the essential channel activity is preserved. Here, we investigated the effect of several inhibitors on recombinant HCV p7 channels corresponding to genotypes 1a–b, 2a–b, 3a and 4a using patch-clamp electrophysiology and cell-based assays. We established a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based cell viability assay for recombinant p7 expressed in HEK293 cells to assess channel activity and its sensitivity to inhibitors. The results from the cell viability assay were consistent with control measurements using established assays of haemadsorption and intracellular pH, and agreed with data from patch-clamp electrophysiology. Hexamethylene amiloride (HMA) was the most potent inhibitor of p7 activity, but possessed cytotoxic activity at higher concentrations. Rimantadine was active against p7 of all genotypes, while amantadine activity was genotype-dependent. The alkyl-chain iminosugars NB-DNJ, NN-DNJ and NN-DGJ were tested and their activity was found to be genotype-specific. In the current study, we introduce cell viability assays as a rapid and cost-efficient technique to assess viroporin activity and identify channel inhibitors as potential novel antiviral drugs.

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Section: Discussionmentioning

confidence: 99%

Cell viability assay as a tool to study activity and inhibition of hepatitis C p7 channels

Breitinger

Farag

Ali

et al. 2021

Journal of General Virology

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“… 94 , 95 A recent study revealed that a p7 ion channel-derived peptide H2-3 potently inhibits HCV entry by directly affecting virus binding to the cell surface and interfering with the virus–host interaction ( Table 1 ). 36 …”

Section: Hcv Entry Into Hepatocytesmentioning

confidence: 99%

Entry inhibitors: New advances in HCV treatment

Qian

Zhu

Zhao

et al. 2016

Emerging Microbes & Infections

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Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry.

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“…Lactoferin, present in milk, also blocks HCV attachment [46] . Like E1/E2, the P7 protein also inhibits HCV entry by directly effecting virus binding to cell surface and interfering with host-virus interaction [47] .…”

Section: Hcv Entry As Targetmentioning

confidence: 99%

Molecular targeting of antiviral drugs used against hepatitis C virus infection

Irshad¹,

Gupta²,

Irshad³

2018

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Present study reports an update on the molecular interaction of antiviral drugs with viral and host cell components during hepatitis C virus (HCV) infection. In addition to the traditional therapeutic drug regimen, termed as standard of care, some recent drugs have been added in the existing regimen used for HCV infection. These drugs were categorized as direct-acting antivirals (DAAs) agents and "other agents", with their efficacious impact in the control of HCV infection. They target both viral proteases and host cell receptor proteins/enzymes involved in HCV entry into the cell, replication, and assembly to check their propagation both in situ as well as in cell to cell transmission. Recent studies have reported a significant rise in sustained virological response after the use of these drugs both alone and in combination with pegylated interferon-α (PegIFN-α) plus ribavirin. Recently, DAAs have been reported to be highly effective in eradication of HCV infection, especially liver cirrhosis, reducing but not avoiding the occurrence of liver cancer. Some studies have demonstrated that the presence of resistant HCV variants, arising during viral replication, may be controlled by the new drug regimen. It is important to note here that all these drugs are influenced by viral as well as host factors including basic viral load, HCV genotypes, IFN action, interleukin 28B polymorphism and some liver and metabolic diseases, etc. This is an area with ongoing investigations to explore more antiviral agents that may address new challenges in HCV therapy.

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A p7 Ion Channel-derived Peptide Inhibits Hepatitis C Virus Infection in Vitro

Cited by 7 publications

References 29 publications

Cell viability assay as a tool to study activity and inhibition of hepatitis C p7 channels

Cell viability assay as a tool to study activity and inhibition of hepatitis C p7 channels

Entry inhibitors: New advances in HCV treatment

Molecular targeting of antiviral drugs used against hepatitis C virus infection

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