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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors</title><author><name sortKey="Bauman, Joseph D" sort="Bauman, Joseph D" uniqKey="Bauman J" first="Joseph D." last="Bauman">Joseph D. Bauman</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Patel, Disha" sort="Patel, Disha" uniqKey="Patel D" first="Disha" last="Patel">Disha Patel</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Baker, Steven F" sort="Baker, Steven F" uniqKey="Baker S" first="Steven F." last="Baker">Steven F. Baker</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff></affiliation></author><author><name sortKey="Vijayan, R S K" sort="Vijayan, R S K" uniqKey="Vijayan R" first="R. S. K." last="Vijayan">R. S. K. Vijayan</name><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Xiang, Amy" sort="Xiang, Amy" uniqKey="Xiang A" first="Amy" last="Xiang">Amy Xiang</name><affiliation><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff></affiliation></author><author><name sortKey="Parhi, Ajit K" sort="Parhi, Ajit K" uniqKey="Parhi A" first="Ajit K." last="Parhi">Ajit K. Parhi</name><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff></affiliation></author><author><name sortKey="Martinez Sobrido, Luis" sort="Martinez Sobrido, Luis" uniqKey="Martinez Sobrido L" first="Luis" last="Martínez-Sobrido">Luis Martínez-Sobrido</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff></affiliation></author><author><name sortKey="Lavoie, Edmond J" sort="Lavoie, Edmond J" uniqKey="Lavoie E" first="Edmond J." last="Lavoie">Edmond J. Lavoie</name><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Das, Kalyan" sort="Das, Kalyan" uniqKey="Das K" first="Kalyan" last="Das">Kalyan Das</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23978130</idno><idno type="pmc">3928712</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928712</idno><idno type="RBID">PMC:3928712</idno><idno type="doi">10.1021/cb400400j</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000816</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000816</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors</title><author><name sortKey="Bauman, Joseph D" sort="Bauman, Joseph D" uniqKey="Bauman J" first="Joseph D." last="Bauman">Joseph D. Bauman</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Patel, Disha" sort="Patel, Disha" uniqKey="Patel D" first="Disha" last="Patel">Disha Patel</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Baker, Steven F" sort="Baker, Steven F" uniqKey="Baker S" first="Steven F." last="Baker">Steven F. Baker</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff></affiliation></author><author><name sortKey="Vijayan, R S K" sort="Vijayan, R S K" uniqKey="Vijayan R" first="R. S. K." last="Vijayan">R. S. K. Vijayan</name><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Xiang, Amy" sort="Xiang, Amy" uniqKey="Xiang A" first="Amy" last="Xiang">Amy Xiang</name><affiliation><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff></affiliation></author><author><name sortKey="Parhi, Ajit K" sort="Parhi, Ajit K" uniqKey="Parhi A" first="Ajit K." last="Parhi">Ajit K. Parhi</name><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff></affiliation></author><author><name sortKey="Martinez Sobrido, Luis" sort="Martinez Sobrido, Luis" uniqKey="Martinez Sobrido L" first="Luis" last="Martínez-Sobrido">Luis Martínez-Sobrido</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff></affiliation></author><author><name sortKey="Lavoie, Edmond J" sort="Lavoie, Edmond J" uniqKey="Lavoie E" first="Edmond J." last="Lavoie">Edmond J. Lavoie</name><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Das, Kalyan" sort="Das, Kalyan" uniqKey="Das K" first="Kalyan" last="Das">Kalyan Das</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author><author><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><affiliation><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff></affiliation></author></analytic><series><title level="j">ACS chemical biology</title><idno type="ISSN">1554-8929</idno><idno type="eISSN">1554-8937</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PA<sub>N</sub>) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PA<sub>N</sub> active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity, was detected in the active site cleft of PA<sub>N</sub> in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC<sub>50</sub> value of 11 nM was found to have an antiviral activity (EC<sub>50</sub>) of 11 μM against PR8 H1N1 influenza A in MDCK cells.</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">101282906</journal-id><journal-id journal-id-type="pubmed-jr-id">33137</journal-id><journal-id journal-id-type="nlm-ta">ACS Chem Biol</journal-id><journal-id journal-id-type="iso-abbrev">ACS Chem. Biol.</journal-id><journal-title-group><journal-title>ACS chemical biology</journal-title></journal-title-group><issn pub-type="ppub">1554-8929</issn><issn pub-type="epub">1554-8937</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23978130</article-id><article-id pub-id-type="pmc">3928712</article-id><article-id pub-id-type="doi">10.1021/cb400400j</article-id><article-id pub-id-type="manuscript">NIHMS525010</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bauman</surname><given-names>Joseph D.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib><contrib contrib-type="author"><name><surname>Patel</surname><given-names>Disha</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Baker</surname><given-names>Steven F.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Vijayan</surname><given-names>R. S. K.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Xiang</surname><given-names>Amy</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Parhi</surname><given-names>Ajit K.</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Martínez-Sobrido</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>LaVoie</surname><given-names>Edmond J.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Das</surname><given-names>Kalyan</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib><contrib contrib-type="author"><name><surname>Arnold</surname><given-names>Eddy</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</aff><aff id="A2"><label>2</label>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</aff><aff id="A3"><label>3</label>Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</aff><aff id="A4"><label>4</label>Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</aff><aff id="A5"><label>5</label>TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</aff><author-notes><corresp id="CR1"><label>*</label>Corresponding authors (E.A. <email>arnold@cabm.rutgers.edu</email>; J.D.B. <email>bauman@cabm.rutgers.edu</email>; K.D. <email>kalyan@cabm.rutgers.edu</email>)</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>11</day><month>12</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>13</day><month>9</month><year>2013</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>11</month><year>2014</year></pub-date><volume>8</volume><issue>11</issue><fpage>2501</fpage><lpage>2508</lpage><pmc-comment>elocation-id from pubmed: 10.1021/cb400400j</pmc-comment>
<abstract><p id="P1">Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PA<sub>N</sub>) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PA<sub>N</sub> active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity, was detected in the active site cleft of PA<sub>N</sub> in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC<sub>50</sub> value of 11 nM was found to have an antiviral activity (EC<sub>50</sub>) of 11 μM against PR8 H1N1 influenza A in MDCK cells.</p></abstract><funding-group><award-group><funding-source country="United States">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</funding-source><award-id>R03 AI099681 || AI</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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