Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.
Identifieur interne : 001288 ( PubMed/Curation ); précédent : 001287; suivant : 001289Synthesis 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
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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. 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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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25440730</PMID><DateCreated><Year>2015</Year><Month>01</Month><Day>12</Day></DateCreated><DateCompleted><Year>2015</Year><Month>07</Month><Day>23</Day></DateCompleted><DateRevised><Year>2017</Year><Month>07</Month><Day>18</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1464-3391</ISSN><JournalIssue CitedMedium="Internet"><Volume>22</Volume><Issue>22</Issue><PubDate><Year>2014</Year><Month>Nov</Month><Day>15</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry</Title><ISOAbbreviation>Bioorg. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.</ArticleTitle><Pagination><MedlinePgn>6490-6502</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bmc.2014.09.019</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Ireland</LastName><ForeName>Alex W</ForeName><Initials>AW</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Gobillot</LastName><ForeName>Theodore A</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gupta</LastName><ForeName>Tushar</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Seguin</LastName><ForeName>Sandlin P</ForeName><Initials>SP</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liang</LastName><ForeName>Mary</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Resnick</LastName><ForeName>Lynn</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goldberg</LastName><ForeName>Margot T</ForeName><Initials>MT</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Manos-Turvey</LastName><ForeName>Alexandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pipas</LastName><ForeName>James M</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wipf</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brodsky</LastName><ForeName>Jeffrey L</ForeName><Initials>JL</Initials><AffiliationInfo><Affiliation>Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 DK079307</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50 GM067082</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>DK79307</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><Agency>Howard Hughes Medical Institute</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal 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MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002470" MajorTopicYN="N">Cell Survival</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D057809" MajorTopicYN="N">HEK293 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D034444" MajorTopicYN="N">Peptoids</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011120" MajorTopicYN="N">Polyomavirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011744" MajorTopicYN="N">Pyrimidinones</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013539" MajorTopicYN="N">Simian virus 40</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054852" MajorTopicYN="N">Small Molecule Libraries</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">NIHMS629082</OtherID><OtherID Source="NLM">PMC4293281</OtherID></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>07</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2014</Year><Month>08</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>09</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>12</Month><Day>3</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>12</Month><Day>3</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>7</Month><Day>24</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25440730</ArticleId><ArticleId IdType="doi">10.1016/j.bmc.2014.09.019</ArticleId><ArticleId IdType="pmc">PMC4293281</ArticleId><ArticleId 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