title: Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells.
abstract: All eight human herpesviruses have a conserved herpesvirus protein kinase (CHPK) that is important for the lytic phase of the viral life cycle. In this study, we show that heat shock protein 90 (Hsp90) interacts directly with each of the eight CHPKs, and we demonstrate that an Hsp90 inhibitor drug, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreases expression of all eight CHPKs in transfected HeLa cells. 17-DMAG also decreases expression the of the endogenous Epstein-Barr virus protein kinase (EBV PK, encoded by the BGLF4 gene) in lytically infected EBV-positive cells and inhibits phosphorylation of several different known EBV PK target proteins. Furthermore, 17-DMAG treatment abrogates expression of the human cytomegalovirus (HCMV) kinase UL97 in HCMV-infected human fibroblasts. Importantly, 17-DMAG treatment decreased the EBV titer approximately 100-fold in lytically infected AGS-Akata cells without causing significant cellular toxicity during the same time frame. Increased EBV PK expression in 17-DMAG-treated AGS-Akata cells did not restore EBV titers, suggesting that 17-DMAG simultaneously targets multiple viral and/or cellular proteins required for efficient viral replication. These results suggest that Hsp90 inhibitors, including 17-DMAG, may be a promising group of drugs that could have profound antiviral effects on herpesviruses.
authors.affiliation: Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
authors.forename: Jillian A
authors.initials: JA
authors.lastname: Bristol
authors.forename: Satoko
authors.initials: S
authors.lastname: Iwahori
authors.forename: Stacy R
authors.initials: SR
authors.lastname: Hagemeier
authors.forename: Qiao
authors.initials: Q
authors.lastname: Meng
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Barlow
authors.forename: Joyce D
authors.initials: JD
authors.lastname: Fingeroth
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kalejta
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Kenney
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D016227:Benzoquinones / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism*; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000378:metabolism*; D019562:Viral Load; D014776:Virus Cultivation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D011494:Protein Kinases