Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs
Identifieur interne : 001489 ( Pmc/Corpus ); précédent : 001488; suivant : 001490Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs
Auteurs : Parmjeet Randhawa ; G. Zeng ; M. Bueno ; A. Salgarkar ; Andrew Lesniak ; K. Isse ; K. Seyb ; A. Perry ; I. Charles ; C. Hustus ; M. Huang ; M. Smith ; Marcie A. GlicksmanSource :
- Antiviral research [ 0166-3542 ] ; 2014.
Abstract
This study evaluates polyomavirus JC (JCV) large T antigen (LTA) as a potential target for drug development. LTA is a hexameric protein with a helicase activity that is powered by ATP binding and hydrolysis. The helicase and ATPase function is critical for viral replication.
Recombinant JCV LTA was produced in an
Five compounds showed non-competitive inhibition of ATPase activity with an EC50 ≤ 15 μM. Modest antiviral activity was demonstrated in an immunofluorescence assay for JCV VP-1 expression in COS7 cells (EC50 15, 18, 20, 27, and 52 μM respectively). The compounds also inhibited viral replication in a real time PCR assay at comparable concentrations. LD50 in the MTS96 and Cell TiterGlo assays was >100 μM for all compounds in COS7 as well as HEK293 cells. However, two compounds inhibited cell proliferation in culture with IC50 values of 43 and 34 μM respectively. Despite substantial amino acid similarity between polyomavirus JC, BK and SV40 proteins, these compounds differ from those previously reported to inhibit SV40 LTA ATPase in chemical structure as well as a non-competitive mechanism of inhibition.
LTA ATPase is a valid target for discovery. Additional screening and chemical optimization is needed to develop clinically useful compounds with less toxicity, which should be measured by metabolic as well as cell proliferation assays.
Url:
DOI: 10.1016/j.antiviral.2014.10.004
PubMed: 25453344
PubMed Central: 4258517
Links to Exploration step
PMC:4258517Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs</title><author><name sortKey="Randhawa, Parmjeet" sort="Randhawa, Parmjeet" uniqKey="Randhawa P" first="Parmjeet" last="Randhawa">Parmjeet Randhawa</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Zeng, G" sort="Zeng, G" uniqKey="Zeng G" first="G." last="Zeng">G. Zeng</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Bueno, M" sort="Bueno, M" uniqKey="Bueno M" first="M." last="Bueno">M. Bueno</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Salgarkar, A" sort="Salgarkar, A" uniqKey="Salgarkar A" first="A." last="Salgarkar">A. Salgarkar</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Lesniak, Andrew" sort="Lesniak, Andrew" uniqKey="Lesniak A" first="Andrew" last="Lesniak">Andrew Lesniak</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Isse, K" sort="Isse, K" uniqKey="Isse K" first="K." last="Isse">K. Isse</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Seyb, K" sort="Seyb, K" uniqKey="Seyb K" first="K." last="Seyb">K. Seyb</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Perry, A" sort="Perry, A" uniqKey="Perry A" first="A." last="Perry">A. Perry</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Charles, I" sort="Charles, I" uniqKey="Charles I" first="I." last="Charles">I. Charles</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Hustus, C" sort="Hustus, C" uniqKey="Hustus C" first="C." last="Hustus">C. Hustus</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, M" sort="Huang, M" uniqKey="Huang M" first="M." last="Huang">M. Huang</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Smith, M" sort="Smith, M" uniqKey="Smith M" first="M." last="Smith">M. Smith</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Glicksman, Marcie A" sort="Glicksman, Marcie A" uniqKey="Glicksman M" first="Marcie A." last="Glicksman">Marcie A. Glicksman</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25453344</idno><idno type="pmc">4258517</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258517</idno><idno type="RBID">PMC:4258517</idno><idno type="doi">10.1016/j.antiviral.2014.10.004</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001489</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001489</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs</title><author><name sortKey="Randhawa, Parmjeet" sort="Randhawa, Parmjeet" uniqKey="Randhawa P" first="Parmjeet" last="Randhawa">Parmjeet Randhawa</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Zeng, G" sort="Zeng, G" uniqKey="Zeng G" first="G." last="Zeng">G. Zeng</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Bueno, M" sort="Bueno, M" uniqKey="Bueno M" first="M." last="Bueno">M. Bueno</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Salgarkar, A" sort="Salgarkar, A" uniqKey="Salgarkar A" first="A." last="Salgarkar">A. Salgarkar</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Lesniak, Andrew" sort="Lesniak, Andrew" uniqKey="Lesniak A" first="Andrew" last="Lesniak">Andrew Lesniak</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Isse, K" sort="Isse, K" uniqKey="Isse K" first="K." last="Isse">K. Isse</name><affiliation><nlm:aff id="A1">University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Seyb, K" sort="Seyb, K" uniqKey="Seyb K" first="K." last="Seyb">K. Seyb</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Perry, A" sort="Perry, A" uniqKey="Perry A" first="A." last="Perry">A. Perry</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Charles, I" sort="Charles, I" uniqKey="Charles I" first="I." last="Charles">I. Charles</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Hustus, C" sort="Hustus, C" uniqKey="Hustus C" first="C." last="Hustus">C. Hustus</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, M" sort="Huang, M" uniqKey="Huang M" first="M." last="Huang">M. Huang</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Smith, M" sort="Smith, M" uniqKey="Smith M" first="M." last="Smith">M. Smith</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Glicksman, Marcie A" sort="Glicksman, Marcie A" uniqKey="Glicksman M" first="Marcie A." last="Glicksman">Marcie A. Glicksman</name><affiliation><nlm:aff id="A2">Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Antiviral research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Introduction</title><p id="P1">This study evaluates polyomavirus JC (JCV) large T antigen (LTA) as a potential target for drug development. LTA is a hexameric protein with a helicase activity that is powered by ATP binding and hydrolysis. The helicase and ATPase function is critical for viral replication.</p></sec><sec id="S2"><title>Methods</title><p id="P2">Recombinant JCV LTA was produced in an <italic>Escherichia coli</italic> based expression plasmid. ATPase activity was measured using the malachite green assay. A high throughput screen was completed using a brain-biased library of 75,000 drug-like compounds selected for physicochemical properties consistent with blood brain barrier permeability.</p></sec><sec id="S3"><title>Results</title><p id="P3">Five compounds showed non-competitive inhibition of ATPase activity with an EC<sub>50</sub> ≤ 15 μM. Modest antiviral activity was demonstrated in an immunofluorescence assay for JCV VP-1 expression in COS7 cells (EC50 15, 18, 20, 27, and 52 μM respectively). The compounds also inhibited viral replication in a real time PCR assay at comparable concentrations. LD<sub>50</sub> in the MTS96 and Cell TiterGlo assays was >100 μM for all compounds in COS7 as well as HEK293 cells. However, two compounds inhibited cell proliferation in culture with IC<sub>50</sub> values of 43 and 34 μM respectively. Despite substantial amino acid similarity between polyomavirus JC, BK and SV40 proteins, these compounds differ from those previously reported to inhibit SV40 LTA ATPase in chemical structure as well as a non-competitive mechanism of inhibition.</p></sec><sec id="S4"><title>Conclusion</title><p id="P4">LTA ATPase is a valid target for discovery. Additional screening and chemical optimization is needed to develop clinically useful compounds with less toxicity, which should be measured by metabolic as well as cell proliferation assays.</p></sec></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">8109699</journal-id><journal-id journal-id-type="pubmed-jr-id">688</journal-id><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res.</journal-id><journal-title-group><journal-title>Antiviral research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25453344</article-id><article-id pub-id-type="pmc">4258517</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2014.10.004</article-id><article-id pub-id-type="manuscript">NIHMS635484</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Randhawa</surname><given-names>Parmjeet</given-names></name><xref ref-type="aff" rid="A1">a</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Zeng</surname><given-names>G.</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Bueno</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Salgarkar</surname><given-names>A.</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Lesniak</surname><given-names>Andrew</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Isse</surname><given-names>K.</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Seyb</surname><given-names>K.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Perry</surname><given-names>A.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Charles</surname><given-names>I.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Hustus</surname><given-names>C.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Glicksman</surname><given-names>Marcie A.</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib></contrib-group><aff id="A1"><label>a</label>University of Pittsburgh, Pittsburgh, PA, USA</aff><aff id="A2"><label>b</label>Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA</aff><author-notes><corresp id="FN1"><label>*</label>Corresponding author at: E737 UPMC-Montefiore Hospital, 3459 Fifth Ave, Pittsburgh, PA 15213, USA. Tel.: +1 412 647 7646. <email>randhawapa@upmc.edu</email> (P. Randhawa)</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>18</day><month>10</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>15</day><month>10</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>12</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>12</month><year>2015</year></pub-date><volume>0</volume><fpage>113</fpage><lpage>119</lpage><pmc-comment>elocation-id from pubmed: 10.1016/j.antiviral.2014.10.004</pmc-comment>
<permissions><copyright-statement>© 2014 Elsevier B.V. All rights reserved.</copyright-statement><copyright-year>2014</copyright-year></permissions><abstract><sec id="S1"><title>Introduction</title><p id="P1">This study evaluates polyomavirus JC (JCV) large T antigen (LTA) as a potential target for drug development. LTA is a hexameric protein with a helicase activity that is powered by ATP binding and hydrolysis. The helicase and ATPase function is critical for viral replication.</p></sec><sec id="S2"><title>Methods</title><p id="P2">Recombinant JCV LTA was produced in an <italic>Escherichia coli</italic> based expression plasmid. ATPase activity was measured using the malachite green assay. A high throughput screen was completed using a brain-biased library of 75,000 drug-like compounds selected for physicochemical properties consistent with blood brain barrier permeability.</p></sec><sec id="S3"><title>Results</title><p id="P3">Five compounds showed non-competitive inhibition of ATPase activity with an EC<sub>50</sub> ≤ 15 μM. Modest antiviral activity was demonstrated in an immunofluorescence assay for JCV VP-1 expression in COS7 cells (EC50 15, 18, 20, 27, and 52 μM respectively). The compounds also inhibited viral replication in a real time PCR assay at comparable concentrations. LD<sub>50</sub> in the MTS96 and Cell TiterGlo assays was >100 μM for all compounds in COS7 as well as HEK293 cells. However, two compounds inhibited cell proliferation in culture with IC<sub>50</sub> values of 43 and 34 μM respectively. Despite substantial amino acid similarity between polyomavirus JC, BK and SV40 proteins, these compounds differ from those previously reported to inhibit SV40 LTA ATPase in chemical structure as well as a non-competitive mechanism of inhibition.</p></sec><sec id="S4"><title>Conclusion</title><p id="P4">LTA ATPase is a valid target for discovery. Additional screening and chemical optimization is needed to develop clinically useful compounds with less toxicity, which should be measured by metabolic as well as cell proliferation assays.</p></sec></abstract><kwd-group><kwd>Polyomavirus JC</kwd><kwd>Large T antigen</kwd><kwd>ATPase</kwd><kwd>Drugs</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Amérique/explor/PittsburghV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001489 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 001489 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Amérique
|area= PittsburghV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:4258517
|texte= Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:25453344" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a PittsburghV1
| This area was generated with Dilib version V0.6.38. |  |