AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication
We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock dow...
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todo:paper_00219541_v231_n10_p2286_Booth2023-10-03T14:23:38Z AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication Booth, L. Roberts, J.L. Ecroyd, H. Tritsch, S.R. Bavari, S. Reid, S.P. Proniuk, S. Zukiwski, A. Jacob, A. Sepúlveda, C.S. Giovannoni, F. García, C.C. Damonte, E. González-Gallego, J. Tuñón, M.J. Dent, P. 2 amino n [4 [5 (2 phenanthrenyl) 3 trifluoromethyl 1h pyrazol 1 yl]phenyl]acetamide adenosine triphosphatase antivirus agent ar 12 beclin 1 chaperone gamma glutamyltransferase glucose regulated protein 78 glucosidase heat shock protein 27 heat shock protein 70 heat shock protein 90 initiation factor 2alpha lactate dehydrogenase lc3 protein mammalian target of rapamycin pazopanib small interfering RNA sorafenib unclassified drug virus protein virus receptor animal experiment Article autophagosome autophagy cell killing cell viability controlled study Coxsackievirus B4 cytolysis Ebolavirus endoplasmic reticulum stress enzyme release experimental rabbit gene overexpression gene silencing human human cell Human immunodeficiency virus immunofluorescence test Influenza virus Junin virus macrophage Measles virus mouse Mumps virus nonhuman priority journal protein dephosphorylation protein glycosylation protein localization protein phosphorylation protein protein interaction Rubella virus virus replication wild type We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α—dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses including Mumps, Influenza, Measles, Junín, Rubella, HIV (wild type and protease resistant), and Ebola, an effect replicated by knock down of multiple chaperone proteins. AR-12—stimulated the co-localization of Influenza, EBV and HIV virus proteins with LC3 in autophagosomes and reduced viral protein association with the chaperones HSP90, HSP70, and GRP78. Knock down of Beclin1 suppressed drug-induced autophagosome formation and reduced the anti-viral protection afforded by AR-12. In an animal model of hemorrhagic fever virus, a transient exposure of animals to low doses of AR-12 doubled animal survival from ∼30% to ∼60% and suppressed liver damage as measured by ATL, GGT and LDH release. Thus through inhibition of chaperone protein functions; reducing the production, stability and processing of viral proteins; and stimulating autophagosome formation/viral protein degradation, AR-12 acts as a broad-specificity anti-viral drug in vitro and in vivo. We argue future patient studies with AR-12 are warranted. J. Cell. Physiol. 231: 2286–2302, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc. Fil:Sepúlveda, C.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:García, C.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Damonte, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00219541_v231_n10_p2286_Booth |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
2 amino n [4 [5 (2 phenanthrenyl) 3 trifluoromethyl 1h pyrazol 1 yl]phenyl]acetamide adenosine triphosphatase antivirus agent ar 12 beclin 1 chaperone gamma glutamyltransferase glucose regulated protein 78 glucosidase heat shock protein 27 heat shock protein 70 heat shock protein 90 initiation factor 2alpha lactate dehydrogenase lc3 protein mammalian target of rapamycin pazopanib small interfering RNA sorafenib unclassified drug virus protein virus receptor animal experiment Article autophagosome autophagy cell killing cell viability controlled study Coxsackievirus B4 cytolysis Ebolavirus endoplasmic reticulum stress enzyme release experimental rabbit gene overexpression gene silencing human human cell Human immunodeficiency virus immunofluorescence test Influenza virus Junin virus macrophage Measles virus mouse Mumps virus nonhuman priority journal protein dephosphorylation protein glycosylation protein localization protein phosphorylation protein protein interaction Rubella virus virus replication wild type |
| spellingShingle |
2 amino n [4 [5 (2 phenanthrenyl) 3 trifluoromethyl 1h pyrazol 1 yl]phenyl]acetamide adenosine triphosphatase antivirus agent ar 12 beclin 1 chaperone gamma glutamyltransferase glucose regulated protein 78 glucosidase heat shock protein 27 heat shock protein 70 heat shock protein 90 initiation factor 2alpha lactate dehydrogenase lc3 protein mammalian target of rapamycin pazopanib small interfering RNA sorafenib unclassified drug virus protein virus receptor animal experiment Article autophagosome autophagy cell killing cell viability controlled study Coxsackievirus B4 cytolysis Ebolavirus endoplasmic reticulum stress enzyme release experimental rabbit gene overexpression gene silencing human human cell Human immunodeficiency virus immunofluorescence test Influenza virus Junin virus macrophage Measles virus mouse Mumps virus nonhuman priority journal protein dephosphorylation protein glycosylation protein localization protein phosphorylation protein protein interaction Rubella virus virus replication wild type Booth, L. Roberts, J.L. Ecroyd, H. Tritsch, S.R. Bavari, S. Reid, S.P. Proniuk, S. Zukiwski, A. Jacob, A. Sepúlveda, C.S. Giovannoni, F. García, C.C. Damonte, E. González-Gallego, J. Tuñón, M.J. Dent, P. AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| topic_facet |
2 amino n [4 [5 (2 phenanthrenyl) 3 trifluoromethyl 1h pyrazol 1 yl]phenyl]acetamide adenosine triphosphatase antivirus agent ar 12 beclin 1 chaperone gamma glutamyltransferase glucose regulated protein 78 glucosidase heat shock protein 27 heat shock protein 70 heat shock protein 90 initiation factor 2alpha lactate dehydrogenase lc3 protein mammalian target of rapamycin pazopanib small interfering RNA sorafenib unclassified drug virus protein virus receptor animal experiment Article autophagosome autophagy cell killing cell viability controlled study Coxsackievirus B4 cytolysis Ebolavirus endoplasmic reticulum stress enzyme release experimental rabbit gene overexpression gene silencing human human cell Human immunodeficiency virus immunofluorescence test Influenza virus Junin virus macrophage Measles virus mouse Mumps virus nonhuman priority journal protein dephosphorylation protein glycosylation protein localization protein phosphorylation protein protein interaction Rubella virus virus replication wild type |
| description |
We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α—dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses including Mumps, Influenza, Measles, Junín, Rubella, HIV (wild type and protease resistant), and Ebola, an effect replicated by knock down of multiple chaperone proteins. AR-12—stimulated the co-localization of Influenza, EBV and HIV virus proteins with LC3 in autophagosomes and reduced viral protein association with the chaperones HSP90, HSP70, and GRP78. Knock down of Beclin1 suppressed drug-induced autophagosome formation and reduced the anti-viral protection afforded by AR-12. In an animal model of hemorrhagic fever virus, a transient exposure of animals to low doses of AR-12 doubled animal survival from ∼30% to ∼60% and suppressed liver damage as measured by ATL, GGT and LDH release. Thus through inhibition of chaperone protein functions; reducing the production, stability and processing of viral proteins; and stimulating autophagosome formation/viral protein degradation, AR-12 acts as a broad-specificity anti-viral drug in vitro and in vivo. We argue future patient studies with AR-12 are warranted. J. Cell. Physiol. 231: 2286–2302, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc. |
| format |
JOUR |
| author |
Booth, L. Roberts, J.L. Ecroyd, H. Tritsch, S.R. Bavari, S. Reid, S.P. Proniuk, S. Zukiwski, A. Jacob, A. Sepúlveda, C.S. Giovannoni, F. García, C.C. Damonte, E. González-Gallego, J. Tuñón, M.J. Dent, P. |
| author_facet |
Booth, L. Roberts, J.L. Ecroyd, H. Tritsch, S.R. Bavari, S. Reid, S.P. Proniuk, S. Zukiwski, A. Jacob, A. Sepúlveda, C.S. Giovannoni, F. García, C.C. Damonte, E. González-Gallego, J. Tuñón, M.J. Dent, P. |
| author_sort |
Booth, L. |
| title |
AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| title_short |
AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| title_full |
AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| title_fullStr |
AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| title_full_unstemmed |
AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication |
| title_sort |
ar-12 inhibits multiple chaperones concomitant with stimulating autophagosome formation collectively preventing virus replication |
| url |
http://hdl.handle.net/20.500.12110/paper_00219541_v231_n10_p2286_Booth |
| work_keys_str_mv |
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