A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation
Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HB...
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| creator | Tang, Jing Huang, Zhi-Min Chen, Ying-Yi Zhang, Zhao-Hui Liu, Gao-Lin Zhang, Jian |
| description | Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy.
This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.
A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells.
Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P |
| doi_str_mv | 10.1371/journal.pone.0036363 |
| format | Article |
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This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.
A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells.
Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P<0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression.
Our findings suggest that anti-HBV activity of HBSC-11 may be mediated by a reduction in hLa levels. In addition, our data suggest the potential clinical use of hLa inhibitors, such as HBSC-11, for treating HBV infection.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0036363</identifier><identifier>PMID: 22558448</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antigens ; Antiviral Agents - pharmacology ; Apoptosis ; Atoms & subatomic particles ; Binding sites ; Biology ; Chemical compounds ; Chemistry ; Computer Science ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; Drug Evaluation, Preclinical ; Education ; Evaluation ; Genomes ; Health aspects ; Hep G2 Cells ; Hepatitis ; Hepatitis B ; Hepatitis B e antigen ; Hepatitis B surface antigen ; Hepatitis B virus - drug effects ; Hepatitis B virus - genetics ; Hepatitis B virus - physiology ; Hepatocellular carcinoma ; Histocompatibility antigen HLA ; Humans ; Inhibition ; Inhibitors ; La protein ; Laboratories ; Leukemia ; Libraries ; Ligands ; Liver ; Liver diseases ; Medical screening ; Medicine ; Models, Molecular ; Molecular docking ; Pharmacology ; Pharmacy ; Phosphoproteins - antagonists & inhibitors ; Phosphoproteins - chemistry ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Protein Conformation ; Proteins ; Replication ; Ribonucleic acid ; RNA ; RNA polymerase ; Transcription ; User-Computer Interface ; Virus Replication - drug effects ; Viruses</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e36363-e36363</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Tang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-9ffc441b1e815cb3dd51b6c0c2fce0224666328b9819eae36057c89c850019743</citedby><cites>FETCH-LOGICAL-c692t-9ffc441b1e815cb3dd51b6c0c2fce0224666328b9819eae36057c89c850019743</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/PMC3338670/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338670/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22558448$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Jing</creatorcontrib><creatorcontrib>Huang, Zhi-Min</creatorcontrib><creatorcontrib>Chen, Ying-Yi</creatorcontrib><creatorcontrib>Zhang, Zhao-Hui</creatorcontrib><creatorcontrib>Liu, Gao-Lin</creatorcontrib><creatorcontrib>Zhang, Jian</creatorcontrib><title>A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy.
This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.
A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells.
Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P<0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression.
Our findings suggest that anti-HBV activity of HBSC-11 may be mediated by a reduction in hLa levels. In addition, our data suggest the potential clinical use of hLa inhibitors, such as HBSC-11, for treating HBV infection.</description><subject>Antigens</subject><subject>Antiviral Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Atoms & subatomic particles</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Chemical compounds</subject><subject>Chemistry</subject><subject>Computer Science</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drug Evaluation, Preclinical</subject><subject>Education</subject><subject>Evaluation</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Hep G2 Cells</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B e antigen</subject><subject>Hepatitis B surface antigen</subject><subject>Hepatitis B virus - drug effects</subject><subject>Hepatitis B virus - genetics</subject><subject>Hepatitis B virus - physiology</subject><subject>Hepatocellular carcinoma</subject><subject>Histocompatibility antigen HLA</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>La protein</subject><subject>Laboratories</subject><subject>Leukemia</subject><subject>Libraries</subject><subject>Ligands</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Medical screening</subject><subject>Medicine</subject><subject>Models, Molecular</subject><subject>Molecular docking</subject><subject>Pharmacology</subject><subject>Pharmacy</subject><subject>Phosphoproteins - antagonists & inhibitors</subject><subject>Phosphoproteins - chemistry</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Replication</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA polymerase</subject><subject>Transcription</subject><subject>User-Computer Interface</subject><subject>Virus Replication - 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pharmacology</topic><topic>Apoptosis</topic><topic>Atoms & subatomic particles</topic><topic>Binding sites</topic><topic>Biology</topic><topic>Chemical compounds</topic><topic>Chemistry</topic><topic>Computer Science</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drug Evaluation, Preclinical</topic><topic>Education</topic><topic>Evaluation</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Hep G2 Cells</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B e antigen</topic><topic>Hepatitis B surface antigen</topic><topic>Hepatitis B virus - drug effects</topic><topic>Hepatitis B virus - genetics</topic><topic>Hepatitis B virus - physiology</topic><topic>Hepatocellular carcinoma</topic><topic>Histocompatibility antigen HLA</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>La protein</topic><topic>Laboratories</topic><topic>Leukemia</topic><topic>Libraries</topic><topic>Ligands</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Medical screening</topic><topic>Medicine</topic><topic>Models, Molecular</topic><topic>Molecular docking</topic><topic>Pharmacology</topic><topic>Pharmacy</topic><topic>Phosphoproteins - 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Academic</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>Tang, Jing</au><au>Huang, Zhi-Min</au><au>Chen, Ying-Yi</au><au>Zhang, Zhao-Hui</au><au>Liu, Gao-Lin</au><au>Zhang, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-27</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e36363</spage><epage>e36363</epage><pages>e36363-e36363</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy.
This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.
A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells.
Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P<0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression.
Our findings suggest that anti-HBV activity of HBSC-11 may be mediated by a reduction in hLa levels. In addition, our data suggest the potential clinical use of hLa inhibitors, such as HBSC-11, for treating HBV infection.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22558448</pmid><doi>10.1371/journal.pone.0036363</doi><tpages>e36363</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-04, Vol.7 (4), p.e36363-e36363 |
| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Antigens Antiviral Agents - pharmacology Apoptosis Atoms & subatomic particles Binding sites Biology Chemical compounds Chemistry Computer Science Cytotoxicity Deoxyribonucleic acid DNA Drug Evaluation, Preclinical Education Evaluation Genomes Health aspects Hep G2 Cells Hepatitis Hepatitis B Hepatitis B e antigen Hepatitis B surface antigen Hepatitis B virus - drug effects Hepatitis B virus - genetics Hepatitis B virus - physiology Hepatocellular carcinoma Histocompatibility antigen HLA Humans Inhibition Inhibitors La protein Laboratories Leukemia Libraries Ligands Liver Liver diseases Medical screening Medicine Models, Molecular Molecular docking Pharmacology Pharmacy Phosphoproteins - antagonists & inhibitors Phosphoproteins - chemistry Phosphoproteins - genetics Phosphoproteins - metabolism Protein Conformation Proteins Replication Ribonucleic acid RNA RNA polymerase Transcription User-Computer Interface Virus Replication - drug effects Viruses |
| title | A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T08%3A50%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20novel%20inhibitor%20of%20human%20La%20protein%20with%20anti-HBV%20activity%20discovered%20by%20structure-based%20virtual%20screening%20and%20in%20vitro%20evaluation&rft.jtitle=PloS%20one&rft.au=Tang,%20Jing&rft.date=2012-04-27&rft.volume=7&rft.issue=4&rft.spage=e36363&rft.epage=e36363&rft.pages=e36363-e36363&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0036363&rft_dat=%3Cgale_plos_%3EA477034025%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1324600404&rft_id=info:pmid/22558448&rft_galeid=A477034025&rft_doaj_id=oai_doaj_org_article_ad4718c412b9424b892deffc71068e26&rfr_iscdi=true |