title: Inhibition of heat-shock protein 90 reduces Ebola virus replication.
abstract: Ebola virus (EBOV), a negative-sense RNA virus in the family Filoviridae, is known to cause severe hemorrhagic fever in humans and other primates. Infection with EBOV causes a high mortality rate and currently there is no FDA-licensed vaccine or therapeutic treatment available. Recently, heat-shock protein 90 (Hsp90), a molecular chaperone, was shown to be an important host factor for the replication of several negative-strand viruses. We tested the effect of several different Hsp90 inhibitors including geldanamycin, radicicol, and 17-allylamino-17-demethoxygeldanamycin (17-AAG; a geldanamycin analog) on the replication of Zaire EBOV. Our results showed that inhibition of Hsp90 significantly reduced the replication of EBOV. Classic Hsp90 inhibitors reduced viral replication with an effective concentration at 50% (EC(50)) in the high nanomolar to low micromolar range, while drugs from a new class of Hsp90 inhibitors showed markedly more potent inhibition. These compounds blocked EBOV replication with an EC(50) in the low nanomolar range and showed significant potency in blocking replication in primary human monocytes. These results validated that Hsp90 is an important host factor for the replication of filoviruses and suggest that Hsp90 inhibitors may be therapeutically effective in treating EBOV infection.
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Virology Division, Fort Detrick, MD, United States.
authors.forename: Darci R
authors.initials: DR
authors.lastname: Smith
authors.forename: Sarah
authors.initials: S
authors.lastname: McCarthy
authors.forename: Andrew
authors.initials: A
authors.lastname: Chrovian
authors.forename: Gene
authors.initials: G
authors.lastname: Olinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Stossel
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.forename: John H
authors.initials: JH
authors.lastname: Connor
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D012367:RNA, Viral / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D012367:RNA, Viral; C112765:tanespimycin; C035359:monorden
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