Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.
Identifieur interne : 001057 ( Main/Exploration ); précédent : 001056; suivant : 001058Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.
Auteurs : Alex W. Ireland [États-Unis] ; Theodore A. Gobillot [États-Unis] ; Tushar Gupta [États-Unis] ; Sandlin P. Seguin [États-Unis] ; Mary Liang [États-Unis] ; Lynn Resnick [États-Unis] ; Margot T. Goldberg [États-Unis] ; Alexandra Manos-Turvey [États-Unis] ; James M. Pipas [États-Unis] ; Peter Wipf [États-Unis] ; Jeffrey L. Brodsky [États-Unis]Source :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2014.
Descripteurs français
- KwdFr :
- Antigènes des virus oncogènes (), Antigènes des virus oncogènes (métabolisme), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Antiviraux (toxicité), Bibliothèques de petites molécules (), Bibliothèques de petites molécules (pharmacologie), Bibliothèques de petites molécules (synthèse chimique), Cellules HEK293, Humains, Liaison aux protéines, Peptoïdes (), Polyomavirus (), Pyrimidinones (), Relation structure-activité, Réplication virale (), Survie cellulaire (), Virus simien 40 (métabolisme).
- MESH :
- métabolisme : Antigènes des virus oncogènes, Virus simien 40.
- pharmacologie : Antiviraux, Bibliothèques de petites molécules.
- synthèse chimique : Antiviraux, Bibliothèques de petites molécules.
- toxicité : Antiviraux.
- Antigènes des virus oncogènes, Bibliothèques de petites molécules, Cellules HEK293, Humains, Liaison aux protéines, Peptoïdes, Polyomavirus, Pyrimidinones, Relation structure-activité, Réplication virale, Survie cellulaire.
English descriptors
- KwdEn :
- Antigens, Viral, Tumor (chemistry), Antigens, Viral, Tumor (metabolism), Antiviral Agents (chemical synthesis), Antiviral Agents (pharmacology), Antiviral Agents (toxicity), Cell Survival (drug effects), HEK293 Cells, Humans, Peptoids (chemistry), Polyomavirus (drug effects), Protein Binding, Pyrimidinones (chemistry), Simian virus 40 (metabolism), Small Molecule Libraries (chemical synthesis), Small Molecule Libraries (chemistry), Small Molecule Libraries (pharmacology), Structure-Activity Relationship, Virus Replication (drug effects).
- MESH :
- chemical , chemical synthesis : Antiviral Agents, Small Molecule Libraries.
- chemical , chemistry : Antigens, Viral, Tumor, Peptoids, Pyrimidinones, Small Molecule Libraries.
- chemical , metabolism : Antigens, Viral, Tumor.
- chemical , pharmacology : Antiviral Agents, Small Molecule Libraries.
- chemical , toxicity : Antiviral Agents.
- drug effects : Cell Survival, Polyomavirus, Virus Replication.
- metabolism : Simian virus 40.
- HEK293 Cells, Humans, Protein Binding, Structure-Activity Relationship.
Abstract
Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone–peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50 μM. To improve upon this scaffold and to develop a structure–activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of 50 μM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of 50 μM. We suggest that the knowledge gained from the structure–activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.
DOI: 10.1016/j.bmc.2014.09.019
PubMed: 25440730
Affiliations:
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Ireland</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Gobillot, Theodore A" sort="Gobillot, Theodore A" uniqKey="Gobillot T" first="Theodore A" last="Gobillot">Theodore A. Gobillot</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Gupta, Tushar" sort="Gupta, Tushar" uniqKey="Gupta T" first="Tushar" last="Gupta">Tushar Gupta</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Seguin, Sandlin P" sort="Seguin, Sandlin P" uniqKey="Seguin S" first="Sandlin P" last="Seguin">Sandlin P. Seguin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Liang, Mary" sort="Liang, Mary" uniqKey="Liang M" first="Mary" last="Liang">Mary Liang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Chemistry, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Resnick, Lynn" sort="Resnick, Lynn" uniqKey="Resnick L" first="Lynn" last="Resnick">Lynn Resnick</name><affiliation wicri:level="2"><nlm:affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Chemistry, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Goldberg, Margot T" sort="Goldberg, Margot T" uniqKey="Goldberg M" first="Margot T" last="Goldberg">Margot T. Goldberg</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Manos Turvey, Alexandra" sort="Manos Turvey, Alexandra" uniqKey="Manos Turvey A" first="Alexandra" last="Manos-Turvey">Alexandra Manos-Turvey</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Pipas, James M" sort="Pipas, James M" uniqKey="Pipas J" first="James M" last="Pipas">James M. Pipas</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><affiliation wicri:level="2"><nlm:affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Chemistry, University of Pittsburgh, Pittsburgh</wicri:cityArea><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Brodsky, Jeffrey L" sort="Brodsky, Jeffrey L" uniqKey="Brodsky J" first="Jeffrey L" last="Brodsky">Jeffrey L. Brodsky</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biological Science, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigens, Viral, Tumor (chemistry)</term><term>Antigens, Viral, Tumor (metabolism)</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (pharmacology)</term><term>Antiviral Agents (toxicity)</term><term>Cell Survival (drug effects)</term><term>HEK293 Cells</term><term>Humans</term><term>Peptoids (chemistry)</term><term>Polyomavirus (drug effects)</term><term>Protein Binding</term><term>Pyrimidinones (chemistry)</term><term>Simian virus 40 (metabolism)</term><term>Small Molecule Libraries (chemical synthesis)</term><term>Small Molecule Libraries (chemistry)</term><term>Small Molecule Libraries (pharmacology)</term><term>Structure-Activity Relationship</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antigènes des virus oncogènes ()</term><term>Antigènes des virus oncogènes (métabolisme)</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Antiviraux (toxicité)</term><term>Bibliothèques de petites molécules ()</term><term>Bibliothèques de petites molécules (pharmacologie)</term><term>Bibliothèques de petites molécules (synthèse chimique)</term><term>Cellules HEK293</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptoïdes ()</term><term>Polyomavirus ()</term><term>Pyrimidinones ()</term><term>Relation structure-activité</term><term>Réplication virale ()</term><term>Survie cellulaire ()</term><term>Virus simien 40 (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antigens, Viral, Tumor</term><term>Peptoids</term><term>Pyrimidinones</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigens, Viral, Tumor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term><term>Polyomavirus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Simian virus 40</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes des virus oncogènes</term><term>Virus simien 40</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Bibliothèques de petites molécules</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term><term>Bibliothèques de petites molécules</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>HEK293 Cells</term><term>Humans</term><term>Protein Binding</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antigènes des virus oncogènes</term><term>Bibliothèques de petites molécules</term><term>Cellules HEK293</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptoïdes</term><term>Polyomavirus</term><term>Pyrimidinones</term><term>Relation structure-activité</term><term>Réplication virale</term><term>Survie cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone–peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50 μM. To improve upon this scaffold and to develop a structure–activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of 50 μM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of 50 μM. We suggest that the knowledge gained from the structure–activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Ireland, Alex W" sort="Ireland, Alex W" uniqKey="Ireland A" first="Alex W" last="Ireland">Alex W. Ireland</name></region><name sortKey="Brodsky, Jeffrey L" sort="Brodsky, Jeffrey L" uniqKey="Brodsky J" first="Jeffrey L" last="Brodsky">Jeffrey L. Brodsky</name><name sortKey="Gobillot, Theodore A" sort="Gobillot, Theodore A" uniqKey="Gobillot T" first="Theodore A" last="Gobillot">Theodore A. Gobillot</name><name sortKey="Goldberg, Margot T" sort="Goldberg, Margot T" uniqKey="Goldberg M" first="Margot T" last="Goldberg">Margot T. Goldberg</name><name sortKey="Gupta, Tushar" sort="Gupta, Tushar" uniqKey="Gupta T" first="Tushar" last="Gupta">Tushar Gupta</name><name sortKey="Liang, Mary" sort="Liang, Mary" uniqKey="Liang M" first="Mary" last="Liang">Mary Liang</name><name sortKey="Manos Turvey, Alexandra" sort="Manos Turvey, Alexandra" uniqKey="Manos Turvey A" first="Alexandra" last="Manos-Turvey">Alexandra Manos-Turvey</name><name sortKey="Pipas, James M" sort="Pipas, James M" uniqKey="Pipas J" first="James M" last="Pipas">James M. Pipas</name><name sortKey="Resnick, Lynn" sort="Resnick, Lynn" uniqKey="Resnick L" first="Lynn" last="Resnick">Lynn Resnick</name><name sortKey="Seguin, Sandlin P" sort="Seguin, Sandlin P" uniqKey="Seguin S" first="Sandlin P" last="Seguin">Sandlin P. Seguin</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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