title: An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target.
abstract: An estimated three billion people are at risk of Dengue virus (DENV) infection worldwide and there are currently no approved therapeutic interventions for DENV infection. Due to the relatively small size of the DENV genome, DENV is reliant on host factors throughout the viral life cycle. The inducible form of Heat Shock Protein 70 (Hsp70i) has been implicated as a host factor in DENV pathogenesis, however the complete role remains to be elucidated. Here we further illustrate the importance of Hsp70i in dengue virus pathogenesis and describe the antiviral activity of the allosteric small molecule inhibitor that is selective for Hsp70i, called HS-72. In monocytes, Hsp70i is expressed at low levels preceding DENV infection, but Hsp70i expression is induced upon DENV infection. Targeting Hsp70i with HS-72, results in a dose dependent reduction in DENV infected monocytes, while cell viability was maintained. HS-72 works to reduce DENV infection by inhibiting the entry stage of the viral life cycle, through disrupting the association of Hsp70i with the DENV receptor complex. This work highlights Hsp70i as an antiviral target and HS-72 as a potential anti-DENV therapeutic agent.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Howe
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Speer
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Loiselle
authors.affiliation: Emerging Infectious Diseases Program, Duke-NUS Graduate and Medical School, Singapore.
authors.forename: Subhash
authors.initials: S
authors.lastname: Vasudevan
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Electronic address: timothy.haystead@dm.duke.edu.
authors.forename: Timothy A J
authors.initials: TA
authors.lastname: Haystead
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003715:Dengue / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009557:Nipecotic Acids / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D020543:Proteome; D040901:Proteomics / Q000379:methods; D011991:Receptors, Virus / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; C000600301:HS-72 compound; D018840:HSP70 Heat-Shock Proteins; D009557:Nipecotic Acids; D020543:Proteome; D011991:Receptors, Virus
keywords: Antiviral target; Antiviral therapy; Dengue virus; Heat shock protein 70; Small molecule inhibitor