skip to main content

DOE PAGESDOE PAGES

Title: Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein

We report that 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. We used surface plasmon resonance detection to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequentlymore » 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.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [2] ;  [4] ;  [5] ;  [5] ;  [6] ;  [7] ;  [7] ;  [8] ;  [6] ;  [9] ;  [1]
  1. American University in Cairo, New Cairo (Egypt)
  2. Univ. of Lille North of France, Lille (France)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. California Inst. of Technology (CalTech), Pasadena, CA (United States)
  5. Rutgers Univ., Piscataway, NJ (United States)
  6. Stanford Univ. Medical Center, Stanford, CA (United States)
  7. Rutgers University-New Jersey Medical School, Newark, NJ (United States)
  8. Scripps Research Inst., La Jolla, FL (United States)
  9. Univ. of California, Davis, CA (United States)
Publication Date:
OSTI Identifier:
1259520
Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 9; Journal Issue: 10; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE; American University in Cairo, Egypt
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES