Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay

Zongyi Hu, Xin Hu, Shanshan He, Hyung Joon Yim, Jingbo Xiao, Manju Swaroop, Cordelle Tanega, Ya Qin Zhang, Guanghui Yi, C. Cheng Kao, Juan Marugan, Marc Ferrer, Wei Zheng, Noel Southall, T. Jake Liang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that target different stages of the HCV life cycle because of various limitations of the current regimens. In this study, we performed a quantitative high throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) of ∼350,000 chemicals for novel HCV inhibitors using our previously developed cell-based HCV infection assay. Following confirmation and structural clustering analysis, we narrowed down to 158 compounds from the initial ∼3000 molecules that showed inhibitory activity for further structural and functional analyses. We were able to assign the majority of these compounds to specific stage(s) in the HCV life cycle. Three of them are direct inhibitors of NS3/4A protease. Most of the compounds appear to act on novel targets in HCV life cycle. Four compounds with novel structure and excellent drug-like properties, three targeting HCV entry and one targeting HCV assembly/secretion, were advanced for further development as lead hits. These compounds represent diverse chemotypes that are potential lead compounds for further optimization and may offer promising candidates for the development of novel therapeutics against HCV infection. In addition, they represent novel molecular probes to explore the complex interactions between HCV and the cells.

Original languageEnglish
Pages (from-to)20-29
Number of pages10
JournalAntiviral Research
Volume124
DOIs
Publication statusPublished - 2015 Dec 1
Externally publishedYes

Fingerprint

Hepacivirus
Infection
Life Cycle Stages
Small Molecule Libraries
Virus Diseases
Virus Assembly
Molecular Probes
Virus Internalization
Interferons
Antiviral Agents
Cluster Analysis
Peptide Hydrolases
Therapeutics

Keywords

  • Antiviral
  • Cell-based assay
  • HCV inhibitors
  • High throughput screening
  • Viral life cycle

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay. / Hu, Zongyi; Hu, Xin; He, Shanshan; Yim, Hyung Joon; Xiao, Jingbo; Swaroop, Manju; Tanega, Cordelle; Zhang, Ya Qin; Yi, Guanghui; Kao, C. Cheng; Marugan, Juan; Ferrer, Marc; Zheng, Wei; Southall, Noel; Liang, T. Jake.

In: Antiviral Research, Vol. 124, 01.12.2015, p. 20-29.

Research output: Contribution to journalArticle

Hu, Z, Hu, X, He, S, Yim, HJ, Xiao, J, Swaroop, M, Tanega, C, Zhang, YQ, Yi, G, Kao, CC, Marugan, J, Ferrer, M, Zheng, W, Southall, N & Liang, TJ 2015, 'Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay', Antiviral Research, vol. 124, pp. 20-29. https://doi.org/10.1016/j.antiviral.2015.10.018
Hu, Zongyi ; Hu, Xin ; He, Shanshan ; Yim, Hyung Joon ; Xiao, Jingbo ; Swaroop, Manju ; Tanega, Cordelle ; Zhang, Ya Qin ; Yi, Guanghui ; Kao, C. Cheng ; Marugan, Juan ; Ferrer, Marc ; Zheng, Wei ; Southall, Noel ; Liang, T. Jake. / Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay. In: Antiviral Research. 2015 ; Vol. 124. pp. 20-29.
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