5′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus
Identifieur interne : 000D46 ( Pmc/Corpus ); précédent : 000D45; suivant : 000D475′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus
Auteurs : Sanjeev Kumar V. Vernekar ; Li Qiu ; Jing Zhang ; Jayakanth Kankanala ; Hongmin Li ; Robert J. Geraghty ; Zhengqiang WangSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2015.
Abstract
West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure–activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive
Url:
DOI: 10.1021/acs.jmedchem.5b00327
PubMed: 25909386
PubMed Central: 4465584
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Vernekar</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Qiu, Li" sort="Qiu, Li" uniqKey="Qiu L" first="Li" last="Qiu">Li Qiu</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><affiliation><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff></affiliation></author><author><name sortKey="Kankanala, Jayakanth" sort="Kankanala, Jayakanth" uniqKey="Kankanala J" first="Jayakanth" last="Kankanala">Jayakanth Kankanala</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Li, Hongmin" sort="Li, Hongmin" uniqKey="Li H" first="Hongmin" last="Li">Hongmin Li</name><affiliation><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States</nlm:aff></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Wang, Zhengqiang" sort="Wang, Zhengqiang" uniqKey="Wang Z" first="Zhengqiang" last="Wang">Zhengqiang Wang</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25909386</idno><idno type="pmc">4465584</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465584</idno><idno type="RBID">PMC:4465584</idno><idno type="doi">10.1021/acs.jmedchem.5b00327</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000D46</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D46</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">5′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus</title><author><name sortKey="Vernekar, Sanjeev Kumar V" sort="Vernekar, Sanjeev Kumar V" uniqKey="Vernekar S" first="Sanjeev Kumar V." last="Vernekar">Sanjeev Kumar V. Vernekar</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Qiu, Li" sort="Qiu, Li" uniqKey="Qiu L" first="Li" last="Qiu">Li Qiu</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><affiliation><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff></affiliation></author><author><name sortKey="Kankanala, Jayakanth" sort="Kankanala, Jayakanth" uniqKey="Kankanala J" first="Jayakanth" last="Kankanala">Jayakanth Kankanala</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Li, Hongmin" sort="Li, Hongmin" uniqKey="Li H" first="Hongmin" last="Li">Hongmin Li</name><affiliation><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States</nlm:aff></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author><author><name sortKey="Wang, Zhengqiang" sort="Wang, Zhengqiang" uniqKey="Wang Z" first="Zhengqiang" last="Wang">Zhengqiang Wang</name><affiliation><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure–activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive <italic>S</italic>-adenosyl-L-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase).</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9716531</journal-id><journal-id journal-id-type="pubmed-jr-id">4938</journal-id><journal-id journal-id-type="nlm-ta">J Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Chem.</journal-id><journal-title-group><journal-title>Journal of medicinal chemistry</journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25909386</article-id><article-id pub-id-type="pmc">4465584</article-id><article-id pub-id-type="doi">10.1021/acs.jmedchem.5b00327</article-id><article-id pub-id-type="manuscript">NIHMS695073</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>5′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Vernekar</surname><given-names>Sanjeev Kumar V.</given-names></name><xref ref-type="aff" rid="A1">†</xref><xref rid="FN2" ref-type="author-notes">∥</xref></contrib><contrib contrib-type="author"><name><surname>Qiu</surname><given-names>Li</given-names></name><xref ref-type="aff" rid="A1">†</xref><xref rid="FN2" ref-type="author-notes">∥</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="A2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Kankanala</surname><given-names>Jayakanth</given-names></name><xref ref-type="aff" rid="A1">†</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Hongmin</given-names></name><xref ref-type="aff" rid="A2">‡</xref><xref ref-type="aff" rid="A3">§</xref></contrib><contrib contrib-type="author"><name><surname>Geraghty</surname><given-names>Robert J.</given-names></name><xref rid="FN1" ref-type="author-notes">*</xref><xref ref-type="aff" rid="A1">†</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Zhengqiang</given-names></name><xref rid="FN1" ref-type="author-notes">*</xref><xref ref-type="aff" rid="A1">†</xref></contrib></contrib-group><aff id="A1"><label>†</label>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</aff><aff id="A2"><label>‡</label>Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</aff><aff id="A3"><label>§</label>Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States</aff><author-notes><corresp id="FN1"><label>*</label><bold>Corresponding Authors:</bold><email>gerag012@umn.edu</email>. Phone: +1 (612) 625-3281 (R.G.). <email>wangx472@umn.edu</email>. Phone: +1 (612) 626-7025 (Z.W.)</corresp><fn id="FN2" fn-type="equal"><label>∥</label><p><bold>Author Contributions</bold></p><p>These authors (S.K.V.V. and L.Q.) contributed equally.</p></fn><fn id="FN4" fn-type="conflict"><p><bold>Notes</bold></p><p>The authors declare no competing financial interest.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>2</day><month>6</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>04</day><month>5</month><year>2015</year></pub-date><pub-date pub-type="ppub"><day>14</day><month>5</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>14</day><month>2</month><year>2016</year></pub-date><volume>58</volume><issue>9</issue><fpage>4016</fpage><lpage>4028</lpage><pmc-comment>elocation-id from pubmed: 10.1021/acs.jmedchem.5b00327</pmc-comment>
<permissions><copyright-statement>© 2015 American Chemical Society</copyright-statement><copyright-year>2015</copyright-year></permissions><abstract id="Abs1"><p id="P1">West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure–activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive <italic>S</italic>-adenosyl-L-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase).</p></abstract><abstract id="Abs2" abstract-type="graphical"><title>Graphical abstract</title><p id="P2"><graphic xlink:href="nihms695073u1.jpg" position="anchor" orientation="portrait"></graphic></p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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