AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication

Laurence Booth, Jane L. Roberts, Heath Ecroyd, Sarah R. Tritsch, Sina Bavari, St Patrick Reid, Stefan Proniuk, Alexander Zukiwski, Abraham Jacob, Claudia S. Sepúlveda, Federico Giovannoni, Cybele C. García, Elsa Damonte, Javier González-Gallego, María J. Tuñón, Paul Dent

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2286-2302
Number of pages17
JournalJournal of Cellular Physiology
Volume231
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    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. (2016). AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication. Journal of Cellular Physiology, 231(10), 2286-2302. https://doi.org/10.1002/jcp.25431