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

Al Olaby, Reem and Cocquerel, Laurence and Zemla, Adam and Saas, Laure and Dubuisson, Jean and Vielmetter, Jost and Marcotrigiano, Joseph and Khan, Abdul Ghafoor and Catalan, Felipe Vences and Perryman, Alexander L. and Freundlich, Joel S. and Forli, Stefano and Levy, Shoshana and Balhorn, Rod and Azzazy, Hassan M. (2014) Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein. PLoS ONE, 9 (10). Art. No. e111333. ISSN 1932-6203. PMCID PMC4214736. http://resolver.caltech.edu/CaltechAUTHORS:20150122-083734277

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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.


Item Type:Article
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http://dx.doi.org/10.1371/journal.pone.0111333DOIArticle
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111333#abstract0PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214736/PubMed CentralArticle
Additional Information:This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Received: May 9, 2014; Accepted: September 23, 2014; Published: October 30, 2014. This work was conducted as part of the first authors PhD thesis work. This work was supported by a Yousif Jameel PhD Fellowship from The American University in Cairo awarded to Reem Al Olaby. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Lucie Feneant for providing the HCVpp used in this work. Biacore support and instrument use was provided by the Protein Expression Center at the California Institute of Technology, Pasadena, CA. We thank Leslie P. Michelson and Ryan Novosielski of the Rutgers University Office of Information Technology, High Performance and Research Computing, for developing and maintaining the Linux cluster at Rutgers University-NJMS and for assisting us with its use. The ligands tested in this study were provided by the National Cancer Institute through its NCI/Developmental Therapeutics Program (DTP) Open Chemical Repository (http://dtp.cancer.gov).
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Yousif Jameel PhD Fellowship, American University in CairoUNSPECIFIED
PubMed Central ID:PMC4214736
Record Number:CaltechAUTHORS:20150122-083734277
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20150122-083734277
Official Citation:Al Olaby RR, Cocquerel L, Zemla A, Saas L, Dubuisson J, et al. (2014) Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein. PLoS ONE 9(10): e111333. doi:10.1371/journal.pone.0111333
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53976
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:22 Jan 2015 20:47
Last Modified:22 Jan 2015 20:47

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