Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein
Identifieur interne : 000355 ( Pmc/Checkpoint ); précédent : 000354; suivant : 000356Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein
Auteurs : Reem R. Al Olaby [Égypte] ; Laurence Cocquerel [France] ; Adam Zemla [États-Unis] ; Laure Saas [France] ; Jean Dubuisson [France] ; Jost Vielmetter [États-Unis] ; Joseph Marcotrigiano [États-Unis] ; Abdul Ghafoor Khan [États-Unis] ; Felipe Vences Catalan [États-Unis] ; Alexander L. Perryman [États-Unis] ; Joel S. Freundlich [États-Unis] ; Stefano Forli [États-Unis] ; Shoshana Levy [États-Unis] ; Rod Balhorn [États-Unis] ; Hassan M. Azzazy [Égypte]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
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.
Url:
DOI: 10.1371/journal.pone.0111333
PubMed: 25357246
PubMed Central: 4214736
Affiliations:
- France, Égypte, États-Unis
- Californie, Hauts-de-France, New Jersey, Nord-Pas-de-Calais
- Lille, New Brunswick (New Jersey)
- Université Rutgers
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PMC:4214736Le document en format XML
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<author><name sortKey="Forli, Stefano" sort="Forli, Stefano" uniqKey="Forli S" first="Stefano" last="Forli">Stefano Forli</name>
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</nlm:aff>
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<author><name sortKey="Levy, Shoshana" sort="Levy, Shoshana" uniqKey="Levy S" first="Shoshana" last="Levy">Shoshana Levy</name>
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</nlm:aff>
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<author><name sortKey="Balhorn, Rod" sort="Balhorn, Rod" uniqKey="Balhorn R" first="Rod" last="Balhorn">Rod Balhorn</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Applied Science, University of California Davis, Davis, CA</wicri:regionArea>
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<author><name sortKey="Azzazy, Hassan M" sort="Azzazy, Hassan M" uniqKey="Azzazy H" first="Hassan M." last="Azzazy">Hassan M. Azzazy</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Chemistry, The American University in Cairo, New Cairo, Egypt</addr-line>
</nlm:aff>
<country xml:lang="fr">Égypte</country>
<wicri:regionArea>Department of Chemistry, The American University in Cairo, New Cairo</wicri:regionArea>
<wicri:noRegion>New Cairo</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint><date when="2014">2014</date>
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<front><div type="abstract" xml:lang="en"><p>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.</p>
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<biblStruct><analytic><author><name sortKey="Hormazabal, L" uniqKey="Hormazabal L">L Hormazabal</name>
</author>
<author><name sortKey="Omer, Lm" uniqKey="Omer L">LM Omer</name>
</author>
<author><name sortKey="Ismail, S" uniqKey="Ismail S">S Ismail</name>
</author>
</analytic>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25357246</article-id>
<article-id pub-id-type="pmc">4214736</article-id>
<article-id pub-id-type="publisher-id">PONE-D-14-20893</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0111333</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology and life sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Protein Structure</subject>
<subj-group><subject>Protein Structure Prediction</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Biochemical Simulations</subject>
<subject>Biomacromolecule-Ligand Interactions</subject>
</subj-group>
</subj-group>
<subj-group><subject>Computational Biology</subject>
</subj-group>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical microbiology</subject>
<subj-group><subject>Microbial pathogens</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Flaviviruses</subject>
<subj-group><subject>Hepatitis C virus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Molecular Biology</subject>
<subj-group><subject>Macromolecular Structure Analysis</subject>
<subject>Molecular Complexes</subject>
</subj-group>
</subj-group>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>ssRNA viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Computer and Information Sciences</subject>
<subj-group><subject>Computer Modeling</subject>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine and health sciences</subject>
<subj-group><subject>Gastroenterology and hepatology</subject>
<subj-group><subject>Liver diseases</subject>
<subj-group><subject>Infectious hepatitis</subject>
<subj-group><subject>Hepatitis C</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Infectious Diseases</subject>
<subj-group><subject>Viral Diseases</subject>
<subj-group><subject>Hepatitis</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein</article-title>
<alt-title alt-title-type="running-head">Novel HCV Drug Lead Targeting the E2 Glycoprotein</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Al Olaby</surname>
<given-names>Reem R.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cocquerel</surname>
<given-names>Laurence</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zemla</surname>
<given-names>Adam</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saas</surname>
<given-names>Laure</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dubuisson</surname>
<given-names>Jean</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vielmetter</surname>
<given-names>Jost</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marcotrigiano</surname>
<given-names>Joseph</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Khan</surname>
<given-names>Abdul Ghafoor</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Catalan</surname>
<given-names>Felipe Vences</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Perryman</surname>
<given-names>Alexander L.</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Freundlich</surname>
<given-names>Joel S.</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Forli</surname>
<given-names>Stefano</given-names>
</name>
<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levy</surname>
<given-names>Shoshana</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Balhorn</surname>
<given-names>Rod</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>10</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
<xref ref-type="author-notes" rid="fn1"><sup>¤</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Azzazy</surname>
<given-names>Hassan M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Chemistry, The American University in Cairo, New Cairo, Egypt</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Pathogen Bioinformatics, Lawrence Livermore National Laboratory, Livermore, CA, United States of America</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Protein Expression Center, Beckman Institute, California Institute of Technology, Pasadena, CA, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America</addr-line>
</aff>
<aff id="aff7"><label>7</label>
<addr-line>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</addr-line>
</aff>
<aff id="aff8"><label>8</label>
<addr-line>Department of Pharmacology and Physiology, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America</addr-line>
</aff>
<aff id="aff9"><label>9</label>
<addr-line>Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, United States of America</addr-line>
</aff>
<aff id="aff10"><label>10</label>
<addr-line>Department of Applied Science, University of California Davis, Davis, CA, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Uversky</surname>
<given-names>Vladimir N.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of South Florida College of Medicine, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>rod@shaltech.com</email>
</corresp>
<fn fn-type="conflict"><p><bold>Competing Interests: </bold>
Reem Al Olaby, Dr. Hassan Azzazy and Dr. Rod Balhorn are co-inventors on a patent application related to the described work that has been submitted by The American University in Cairo, Cairo, Egypt. The title for the application is Ligands That Target Hepatitis C Virus E2 Protein. None of the other coauthors have competing interests. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: RRA LC AZ JD JV JM JSF SF SL RB HMA. Performed the experiments: RRA AZ LS AGK FVC ALP SF. Analyzed the data: RRA LC AZ JV AGK FVC ALP SF RB. Contributed reagents/materials/analysis tools: RRA JD JV JM JSF SL HMA. Contributed to the writing of the manuscript: RRA LC AZ RB.</p>
</fn>
<fn id="fn1" fn-type="current-aff"><label>¤</label>
<p>Current address: SHAL Technologies Inc., Livermore, CA, United States of America</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>30</day>
<month>10</month>
<year>2014</year>
</pub-date>
<volume>9</volume>
<issue>10</issue>
<elocation-id>e111333</elocation-id>
<history><date date-type="received"><day>9</day>
<month>5</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>23</day>
<month>9</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-year>2014</copyright-year>
<license><license-p>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.</license-p>
</license>
</permissions>
<abstract><p>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.</p>
</abstract>
<funding-group><funding-statement>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.</funding-statement>
</funding-group>
<counts><page-count count="20"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>France</li>
<li>Égypte</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Hauts-de-France</li>
<li>New Jersey</li>
<li>Nord-Pas-de-Calais</li>
</region>
<settlement><li>Lille</li>
<li>New Brunswick (New Jersey)</li>
</settlement>
<orgName><li>Université Rutgers</li>
</orgName>
</list>
<tree><country name="Égypte"><noRegion><name sortKey="Al Olaby, Reem R" sort="Al Olaby, Reem R" uniqKey="Al Olaby R" first="Reem R." last="Al Olaby">Reem R. Al Olaby</name>
</noRegion>
<name sortKey="Azzazy, Hassan M" sort="Azzazy, Hassan M" uniqKey="Azzazy H" first="Hassan M." last="Azzazy">Hassan M. Azzazy</name>
</country>
<country name="France"><region name="Hauts-de-France"><name sortKey="Cocquerel, Laurence" sort="Cocquerel, Laurence" uniqKey="Cocquerel L" first="Laurence" last="Cocquerel">Laurence Cocquerel</name>
</region>
<name sortKey="Dubuisson, Jean" sort="Dubuisson, Jean" uniqKey="Dubuisson J" first="Jean" last="Dubuisson">Jean Dubuisson</name>
<name sortKey="Saas, Laure" sort="Saas, Laure" uniqKey="Saas L" first="Laure" last="Saas">Laure Saas</name>
</country>
<country name="États-Unis"><region name="Californie"><name sortKey="Zemla, Adam" sort="Zemla, Adam" uniqKey="Zemla A" first="Adam" last="Zemla">Adam Zemla</name>
</region>
<name sortKey="Balhorn, Rod" sort="Balhorn, Rod" uniqKey="Balhorn R" first="Rod" last="Balhorn">Rod Balhorn</name>
<name sortKey="Catalan, Felipe Vences" sort="Catalan, Felipe Vences" uniqKey="Catalan F" first="Felipe Vences" last="Catalan">Felipe Vences Catalan</name>
<name sortKey="Forli, Stefano" sort="Forli, Stefano" uniqKey="Forli S" first="Stefano" last="Forli">Stefano Forli</name>
<name sortKey="Freundlich, Joel S" sort="Freundlich, Joel S" uniqKey="Freundlich J" first="Joel S." last="Freundlich">Joel S. Freundlich</name>
<name sortKey="Freundlich, Joel S" sort="Freundlich, Joel S" uniqKey="Freundlich J" first="Joel S." last="Freundlich">Joel S. Freundlich</name>
<name sortKey="Khan, Abdul Ghafoor" sort="Khan, Abdul Ghafoor" uniqKey="Khan A" first="Abdul Ghafoor" last="Khan">Abdul Ghafoor Khan</name>
<name sortKey="Levy, Shoshana" sort="Levy, Shoshana" uniqKey="Levy S" first="Shoshana" last="Levy">Shoshana Levy</name>
<name sortKey="Marcotrigiano, Joseph" sort="Marcotrigiano, Joseph" uniqKey="Marcotrigiano J" first="Joseph" last="Marcotrigiano">Joseph Marcotrigiano</name>
<name sortKey="Perryman, Alexander L" sort="Perryman, Alexander L" uniqKey="Perryman A" first="Alexander L." last="Perryman">Alexander L. Perryman</name>
<name sortKey="Vielmetter, Jost" sort="Vielmetter, Jost" uniqKey="Vielmetter J" first="Jost" last="Vielmetter">Jost Vielmetter</name>
</country>
</tree>
</affiliations>
</record>
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