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PLoS One. 2014 Oct 30;9(10):e111333. doi: 10.1371/journal.pone.0111333. eCollection 2014.

Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein.

Author information

1
Department of Chemistry, The American University in Cairo, New Cairo, Egypt.
2
Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France.
3
Pathogen Bioinformatics, Lawrence Livermore National Laboratory, Livermore, CA, United States of America.
4
Protein Expression Center, Beckman Institute, California Institute of Technology, Pasadena, CA, United States of America.
5
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America.
6
Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America.
7
Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America.
8
Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America; Department of Pharmacology and Physiology, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America.
9
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, United States of America.
10
Department of Applied Science, University of California Davis, Davis, CA, United States of America.

Abstract

Hepatitis C Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin. Recently, two crystal structures of the core of the HCV E2 protein (E2c) have been determined, providing structural information that can now be used to target the E2 protein and develop drugs that disrupt the early stages of HCV infection by blocking E2's interaction with different host factors. Using the E2c structure as a template, we have created a structural model of the E2 protein core (residues 421-645) that contains the three amino acid segments that are not present in either structure. Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction. Surface plasmon resonance detection was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of Huh-7 cells by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited HCV infection in a genotype-independent manner with IC50's ranging from 2.2 µM to 4.6 µM. 281816 blocked the early and late steps of cell-free HCV entry and also abrogated the cell-to-cell transmission of HCV. Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.

PMID:
25357246
PMCID:
PMC4214736
DOI:
10.1371/journal.pone.0111333
[Indexed for MEDLINE]
Free PMC Article

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