Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein
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...
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creator | Al Olaby, Reem R Cocquerel, Laurence Zemla, Adam Saas, Laure Dubuisson, Jean Vielmetter, Jost Marcotrigiano, Joseph Khan, Abdul Ghafoor Vences Catalan, Felipe Perryman, Alexander L Freundlich, Joel S Forli, Stefano Levy, Shoshana Balhorn, Rod Azzazy, Hassan M |
description | 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. |
doi_str_mv | 10.1371/journal.pone.0111333 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0111333</identifier><identifier>PMID: 25357246</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>60 APPLIED LIFE SCIENCES ; Acids ; Amino Acid Sequence ; Amino acids ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Binders ; Binding ; Binding Sites ; Biological response modifiers ; Biology ; Biology and life sciences ; CD81 antigen ; Cell Line, Tumor ; Cell Survival - drug effects ; Chemistry ; Computer and Information Sciences ; Computer applications ; Crystal structure ; Crystallography, X-Ray ; Development and progression ; Docking ; Drug approval ; Drug delivery ; Drugs ; E2 protein ; Genomes ; Genotype ; Genotype & phenotype ; Genotypes ; Glycoproteins ; Health aspects ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepatitis ; Hepatitis C ; Hepatitis C - drug therapy ; Hepatitis C - pathology ; Hepatitis C - virology ; Hepatitis C virus ; Humans ; Infection ; Infections ; Infectious diseases ; Interferon ; Kinetics ; Ligands ; Liver cirrhosis ; Medicine ; Medicine and health sciences ; Models, Molecular ; Molecular Sequence Data ; Pathogens ; Pharmaceutical industry ; Polymerase ; Proteases ; Protein binding ; Protein Binding - drug effects ; Proteins ; Recombinant Proteins - metabolism ; Residues ; Ribavirin ; Serine ; Serine proteinase ; Structural Homology, Protein ; Surface Plasmon Resonance ; Tetraspanin 28 - metabolism ; Thermodynamics ; Vaccines ; Viral Envelope Proteins - chemistry ; Viral Envelope Proteins - metabolism ; Virus Internalization - drug effects ; Viruses</subject><ispartof>PloS one, 2014-10, Vol.9 (10), p.e111333-e111333</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014. 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. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c719t-539d9e655b2ccdaca095151efc3a09c3077384d88a0c59b1538594418655b3543</citedby><cites>FETCH-LOGICAL-c719t-539d9e655b2ccdaca095151efc3a09c3077384d88a0c59b1538594418655b3543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214736/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214736/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25357246$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1259520$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><contributor>Uversky, Vladimir N.</contributor><creatorcontrib>Al Olaby, Reem R</creatorcontrib><creatorcontrib>Cocquerel, Laurence</creatorcontrib><creatorcontrib>Zemla, Adam</creatorcontrib><creatorcontrib>Saas, Laure</creatorcontrib><creatorcontrib>Dubuisson, Jean</creatorcontrib><creatorcontrib>Vielmetter, Jost</creatorcontrib><creatorcontrib>Marcotrigiano, Joseph</creatorcontrib><creatorcontrib>Khan, Abdul Ghafoor</creatorcontrib><creatorcontrib>Vences Catalan, Felipe</creatorcontrib><creatorcontrib>Perryman, Alexander L</creatorcontrib><creatorcontrib>Freundlich, Joel S</creatorcontrib><creatorcontrib>Forli, Stefano</creatorcontrib><creatorcontrib>Levy, Shoshana</creatorcontrib><creatorcontrib>Balhorn, Rod</creatorcontrib><creatorcontrib>Azzazy, Hassan M</creatorcontrib><creatorcontrib>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</creatorcontrib><title>Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Acids</subject><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Binders</subject><subject>Binding</subject><subject>Binding Sites</subject><subject>Biological response modifiers</subject><subject>Biology</subject><subject>Biology and life sciences</subject><subject>CD81 antigen</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chemistry</subject><subject>Computer and Information Sciences</subject><subject>Computer applications</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Development and progression</subject><subject>Docking</subject><subject>Drug approval</subject><subject>Drug delivery</subject><subject>Drugs</subject><subject>E2 protein</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Genotypes</subject><subject>Glycoproteins</subject><subject>Health aspects</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C - drug therapy</subject><subject>Hepatitis C - pathology</subject><subject>Hepatitis C - virology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Infection</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Interferon</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Liver cirrhosis</subject><subject>Medicine</subject><subject>Medicine and health sciences</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Pathogens</subject><subject>Pharmaceutical industry</subject><subject>Polymerase</subject><subject>Proteases</subject><subject>Protein binding</subject><subject>Protein Binding - drug effects</subject><subject>Proteins</subject><subject>Recombinant Proteins - metabolism</subject><subject>Residues</subject><subject>Ribavirin</subject><subject>Serine</subject><subject>Serine proteinase</subject><subject>Structural Homology, Protein</subject><subject>Surface Plasmon Resonance</subject><subject>Tetraspanin 28 - metabolism</subject><subject>Thermodynamics</subject><subject>Vaccines</subject><subject>Viral Envelope Proteins - chemistry</subject><subject>Viral Envelope Proteins - metabolism</subject><subject>Virus Internalization - drug effects</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNU01v1DAQjRCIloV_gMACCcEhS2zHSXxBqlaFrlSpEh-9Wo7jJF557a3tVPTKL8fZTasN6gHl4K_33sy8ySTJa5gtIS7h540dnOF6ubNGLjMIIcb4SXIKKUZpgTL89Gh_krzwfpNlBFdF8Tw5QQSTEuXFafJn3UgTVKsED8oaYFvAgbG3UoPGDR3Qkjcg9DwAZXpVq-DBxeo6Hlop9gRuGiCk1mmw6biC4LjxW-X9-FrfgcBdJ4MyXZSRe_I5Ap2-E3bnbJDKvEyetVx7-WpaF8mvr-c_Vxfp5dW39ersMhUlpCElmDZUFoTUSIiGC55RAgmUrcBxK3BWlrjKm6rimSC0hrFWQvMcViMFkxwvkrcH3Z22nk32eQYLWFU4qhcRsT4gGss3bOfUlrs7Zrli-wvrOsZdUEJLVtVF1RYVhQWmeVkWdXQZUQTLTGDUCh61vkzRhnorGxFddlzPROcvRvWss7csRzAv8ZjMu4OA9UExL1SQohfWmGg8g4hQEkMuko9TFGdvBukDi86PbeBG2mFfHMWwImjUe_8P9HELJlTHY5WxzTYmJ0ZRdpbDEuY5rUhELR9Bxa-RWxVzlK2K9zPCpxkhYoL8HTo-eM_WP77_P_bqeo79cITtJdeh91YP46_p58D8ABTOeu9k-9AJmLFxnu7dYOM8sWmeIu3NcRcfSPcDhP8C-E8YgA</recordid><startdate>20141030</startdate><enddate>20141030</enddate><creator>Al Olaby, Reem R</creator><creator>Cocquerel, Laurence</creator><creator>Zemla, Adam</creator><creator>Saas, Laure</creator><creator>Dubuisson, Jean</creator><creator>Vielmetter, Jost</creator><creator>Marcotrigiano, Joseph</creator><creator>Khan, Abdul Ghafoor</creator><creator>Vences Catalan, Felipe</creator><creator>Perryman, Alexander L</creator><creator>Freundlich, Joel S</creator><creator>Forli, Stefano</creator><creator>Levy, Shoshana</creator><creator>Balhorn, Rod</creator><creator>Azzazy, Hassan M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141030</creationdate><title>Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein</title><author>Al Olaby, Reem R ; Cocquerel, Laurence ; Zemla, Adam ; Saas, Laure ; Dubuisson, Jean ; Vielmetter, Jost ; Marcotrigiano, Joseph ; Khan, Abdul Ghafoor ; Vences Catalan, Felipe ; Perryman, Alexander L ; Freundlich, Joel S ; Forli, Stefano ; Levy, Shoshana ; Balhorn, Rod ; Azzazy, Hassan M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c719t-539d9e655b2ccdaca095151efc3a09c3077384d88a0c59b1538594418655b3543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Acids</topic><topic>Amino Acid Sequence</topic><topic>Amino acids</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Binders</topic><topic>Binding</topic><topic>Binding Sites</topic><topic>Biological response modifiers</topic><topic>Biology</topic><topic>Biology and life sciences</topic><topic>CD81 antigen</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chemistry</topic><topic>Computer and Information Sciences</topic><topic>Computer applications</topic><topic>Crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Development and progression</topic><topic>Docking</topic><topic>Drug approval</topic><topic>Drug delivery</topic><topic>Drugs</topic><topic>E2 protein</topic><topic>Genomes</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Genotypes</topic><topic>Glycoproteins</topic><topic>Health aspects</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - genetics</topic><topic>Hepatitis</topic><topic>Hepatitis C</topic><topic>Hepatitis C - drug therapy</topic><topic>Hepatitis C - pathology</topic><topic>Hepatitis C - virology</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Infection</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Interferon</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Liver cirrhosis</topic><topic>Medicine</topic><topic>Medicine and health sciences</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Pathogens</topic><topic>Pharmaceutical industry</topic><topic>Polymerase</topic><topic>Proteases</topic><topic>Protein binding</topic><topic>Protein Binding - drug effects</topic><topic>Proteins</topic><topic>Recombinant Proteins - metabolism</topic><topic>Residues</topic><topic>Ribavirin</topic><topic>Serine</topic><topic>Serine proteinase</topic><topic>Structural Homology, Protein</topic><topic>Surface Plasmon Resonance</topic><topic>Tetraspanin 28 - metabolism</topic><topic>Thermodynamics</topic><topic>Vaccines</topic><topic>Viral Envelope Proteins - chemistry</topic><topic>Viral Envelope Proteins - metabolism</topic><topic>Virus Internalization - drug effects</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Al Olaby, Reem R</creatorcontrib><creatorcontrib>Cocquerel, Laurence</creatorcontrib><creatorcontrib>Zemla, Adam</creatorcontrib><creatorcontrib>Saas, Laure</creatorcontrib><creatorcontrib>Dubuisson, Jean</creatorcontrib><creatorcontrib>Vielmetter, Jost</creatorcontrib><creatorcontrib>Marcotrigiano, Joseph</creatorcontrib><creatorcontrib>Khan, Abdul Ghafoor</creatorcontrib><creatorcontrib>Vences Catalan, Felipe</creatorcontrib><creatorcontrib>Perryman, Alexander L</creatorcontrib><creatorcontrib>Freundlich, Joel S</creatorcontrib><creatorcontrib>Forli, Stefano</creatorcontrib><creatorcontrib>Levy, Shoshana</creatorcontrib><creatorcontrib>Balhorn, Rod</creatorcontrib><creatorcontrib>Azzazy, Hassan M</creatorcontrib><creatorcontrib>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Al Olaby, Reem R</au><au>Cocquerel, Laurence</au><au>Zemla, Adam</au><au>Saas, Laure</au><au>Dubuisson, Jean</au><au>Vielmetter, Jost</au><au>Marcotrigiano, Joseph</au><au>Khan, Abdul Ghafoor</au><au>Vences Catalan, Felipe</au><au>Perryman, Alexander L</au><au>Freundlich, Joel S</au><au>Forli, Stefano</au><au>Levy, Shoshana</au><au>Balhorn, Rod</au><au>Azzazy, Hassan M</au><au>Uversky, Vladimir N.</au><aucorp>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-10-30</date><risdate>2014</risdate><volume>9</volume><issue>10</issue><spage>e111333</spage><epage>e111333</epage><pages>e111333-e111333</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25357246</pmid><doi>10.1371/journal.pone.0111333</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2014-10, Vol.9 (10), p.e111333-e111333 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1618835396 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | 60 APPLIED LIFE SCIENCES Acids Amino Acid Sequence Amino acids Antiviral Agents - chemistry Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Binders Binding Binding Sites Biological response modifiers Biology Biology and life sciences CD81 antigen Cell Line, Tumor Cell Survival - drug effects Chemistry Computer and Information Sciences Computer applications Crystal structure Crystallography, X-Ray Development and progression Docking Drug approval Drug delivery Drugs E2 protein Genomes Genotype Genotype & phenotype Genotypes Glycoproteins Health aspects Hepacivirus - drug effects Hepacivirus - genetics Hepatitis Hepatitis C Hepatitis C - drug therapy Hepatitis C - pathology Hepatitis C - virology Hepatitis C virus Humans Infection Infections Infectious diseases Interferon Kinetics Ligands Liver cirrhosis Medicine Medicine and health sciences Models, Molecular Molecular Sequence Data Pathogens Pharmaceutical industry Polymerase Proteases Protein binding Protein Binding - drug effects Proteins Recombinant Proteins - metabolism Residues Ribavirin Serine Serine proteinase Structural Homology, Protein Surface Plasmon Resonance Tetraspanin 28 - metabolism Thermodynamics Vaccines Viral Envelope Proteins - chemistry Viral Envelope Proteins - metabolism Virus Internalization - drug effects Viruses |
title | Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein |
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