Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

Hu, Zongyi; Lan, Keng‐Li; He, Shanshan; Swaroop, Manju; Hu, Xin; Southall, Noel; Zheng, Wei; Liang, T. Jake

doi:10.1128/aac.02529-14

Cited by 9 publications

(17 citation statements)

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“…A). Flunarizine has recently emerged as an anti‐HCV inhibitor in independent screening campaigns . However, its mode of action remains unclear.…”

Section: Resultsmentioning

confidence: 99%

“…However, HCVpp carrying the same viral envelope proteins as flunarizine‐susceptible HCVcc particles are not inhibited by flunarizine, arguing against this. Also, Chockalingam et al and Hu et al reported resistance of HCVpp to flunarizine, leading them to conclude that flunarizine is likely not an entry inhibitor. Our data, however, show that flunarizine inhibits entry of authentic HCV at the stage of membrane fusion.…”

Section: Discussionmentioning

confidence: 99%

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Flunarizine prevents hepatitis C virus membrane fusion in a genotype‐dependent manner by targeting the potential fusion peptide within E1

et al. 2015

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To explore mechanisms of hepatitis C virus (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. Conclusion: These observations reveal novel details about HCV membrane fusion. Moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as cost-effective component of HCV combination therapies.

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“…A). Flunarizine has recently emerged as an anti‐HCV inhibitor in independent screening campaigns . However, its mode of action remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Flunarizine prevents hepatitis C virus membrane fusion in a genotype‐dependent manner by targeting the potential fusion peptide within E1

et al. 2015

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“…Therapeutic regimens are not chosen solely based on patient needs but are determined by what resources are available from the point of view of the health care provider. Advancements in HCV cell culture systems allowed us to approach this problem from a phenotypic perspective, to develop treatments that have a different mode of action from the existing DAAs, and are thus likely synergistic with currently available drugs due to their mechanism of action [21][22][23]. We have previously shown that CCZ inhibits the entry step of HCV infection and exhibits synergistic activity with currently approved anti-HCV agents in vitro [14,24].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

Rolt

et al. 2018

The Journal of Infectious Diseases

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Hepatitis C virus (HCV) is a small, single-stranded, positive-sense RNA virus that infects more than an estimated 70 million people worldwide. Untreated, persistent HCV infection often results in chronic hepatitis, cirrhosis, or liver failure, with progression to hepatocellular carcinoma. Current anti-HCV regimens comprising direct acting antivirals (DAAs) can provide curative treatment; however, due to high costs there remains a need for effective, shorter-duration, and affordable treatments. Recently, we disclosed anti-HCV activity of the cheap antihistamine chlorcyclizine, targeting viral entry. Following our hit-to-lead optimization campaign, we report evaluation of preclinical in vitro absorption, distribution, metabolism, and excretion properties, and in vivo pharmacokinetic profiles of lead compounds. This led to selection of a new lead compound and evaluation of efficacy in chimeric mice engrafted with primary human hepatocytes infected with HCV. Further development and incorporation of this compound into DAA regimens has the potential to improve treatment efficacy, affordability, and accessibility.

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“…The lack of mechanistic information about HCV-mediated fusion has not impeded the discovery of small-molecule inhibitors of HCV fusion. Phenotypic assays using a Cre-Lox-based reporter system to detect HCV infection of cells based on Gaussia luciferase reporter activity enabled discovery of small molecules that act at any step in the viral replication cycle (158). Multiple compounds affecting an early step in the replication cycle were identified from an ∼350,000member library (159).…”

Section: Hepatitis C Virusmentioning

confidence: 99%

Small-Molecule Inhibition of Viral Fusion Glycoproteins

Liu

Yang

2021

Annu. Rev. Virol.

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Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds

Cited by 9 publications

References 0 publications

Flunarizine prevents hepatitis C virus membrane fusion in a genotype‐dependent manner by targeting the potential fusion peptide within E1

Flunarizine prevents hepatitis C virus membrane fusion in a genotype‐dependent manner by targeting the potential fusion peptide within E1

Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

Small-Molecule Inhibition of Viral Fusion Glycoproteins

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