Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors
Identifieur interne : 000899 ( Main/Exploration ); précédent : 000898; suivant : 000900Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors
Auteurs : Joseph D. Bauman [États-Unis] ; Disha Patel [États-Unis] ; Steven F. Baker [États-Unis] ; R. S. K. Vijayan [États-Unis] ; Amy Xiang [États-Unis] ; Ajit K. Parhi [États-Unis] ; Luis Martínez-Sobrido [États-Unis] ; Edmond J. Lavoie [États-Unis] ; Kalyan Das [États-Unis] ; Eddy Arnold [États-Unis]Source :
- ACS chemical biology [ 1554-8929 ] ; 2013.
Abstract
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 (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN 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 PAN 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 IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.
Url:
DOI: 10.1021/cb400400j
PubMed: 23978130
PubMed Central: 3928712
Affiliations:
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Bauman</name><affiliation wicri:level="4"><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Patel, Disha" sort="Patel, Disha" uniqKey="Patel D" first="Disha" last="Patel">Disha Patel</name><affiliation wicri:level="4"><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></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 wicri:level="1"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642</wicri:regionArea><wicri:noRegion>New York 14642</wicri:noRegion></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 wicri:level="4"><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Xiang, Amy" sort="Xiang, Amy" uniqKey="Xiang A" first="Amy" last="Xiang">Amy Xiang</name><affiliation wicri:level="1"><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902</wicri:regionArea><wicri:noRegion>New Jersey 08902</wicri:noRegion></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 wicri:level="4"><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>TAXIS Pharmaceuticals Inc., North Brunswick, New Jersey 08902</wicri:regionArea><wicri:noRegion>New Jersey 08902</wicri:noRegion></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 wicri:level="1"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642</wicri:regionArea><wicri:noRegion>New York 14642</wicri:noRegion></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 wicri:level="4"><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Das, Kalyan" sort="Das, Kalyan" uniqKey="Das K" first="Kalyan" last="Das">Kalyan Das</name><affiliation wicri:level="4"><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><affiliation wicri:level="4"><nlm:aff id="A1">Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="A3">Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, Rutgers University, Piscataway, New Jersey 08854</wicri:regionArea><orgName type="university">Université Rutgers</orgName><placeName><settlement type="city">New Brunswick (New Jersey)</settlement><region type="state">New Jersey</region></placeName></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><affiliations><list><country><li>États-Unis</li></country><region><li>New Jersey</li></region><settlement><li>New Brunswick (New Jersey)</li></settlement><orgName><li>Université Rutgers</li></orgName></list><tree><country name="États-Unis"><region name="New Jersey"><name sortKey="Bauman, Joseph D" sort="Bauman, Joseph D" uniqKey="Bauman J" first="Joseph D." last="Bauman">Joseph D. Bauman</name></region><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><name sortKey="Arnold, Eddy" sort="Arnold, Eddy" uniqKey="Arnold E" first="Eddy" last="Arnold">Eddy Arnold</name><name sortKey="Baker, Steven F" sort="Baker, Steven F" uniqKey="Baker S" first="Steven F." last="Baker">Steven F. Baker</name><name sortKey="Bauman, Joseph D" sort="Bauman, Joseph D" uniqKey="Bauman J" first="Joseph D." last="Bauman">Joseph D. Bauman</name><name sortKey="Das, Kalyan" sort="Das, Kalyan" uniqKey="Das K" first="Kalyan" last="Das">Kalyan Das</name><name sortKey="Das, Kalyan" sort="Das, Kalyan" uniqKey="Das K" first="Kalyan" last="Das">Kalyan Das</name><name sortKey="Lavoie, Edmond J" sort="Lavoie, Edmond J" uniqKey="Lavoie E" first="Edmond J." last="Lavoie">Edmond J. Lavoie</name><name sortKey="Martinez Sobrido, Luis" sort="Martinez Sobrido, Luis" uniqKey="Martinez Sobrido L" first="Luis" last="Martínez-Sobrido">Luis Martínez-Sobrido</name><name sortKey="Parhi, Ajit K" sort="Parhi, Ajit K" uniqKey="Parhi A" first="Ajit K." last="Parhi">Ajit K. Parhi</name><name sortKey="Parhi, Ajit K" sort="Parhi, Ajit K" uniqKey="Parhi A" first="Ajit K." last="Parhi">Ajit K. Parhi</name><name sortKey="Patel, Disha" sort="Patel, Disha" uniqKey="Patel D" first="Disha" last="Patel">Disha Patel</name><name sortKey="Patel, Disha" sort="Patel, Disha" uniqKey="Patel D" first="Disha" last="Patel">Disha Patel</name><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><name sortKey="Xiang, Amy" sort="Xiang, Amy" uniqKey="Xiang A" first="Amy" last="Xiang">Amy Xiang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:23978130" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a H2N2V1
| This area was generated with Dilib version V0.6.33. |  |