title: Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus.
abstract: The movement of proteins between the cytoplasm and nucleus mediated by the importin superfamily of proteins is essential to many cellular processes, including differentiation and development, and is critical to disease states such as viral disease and oncogenesis. We recently developed a high-throughput screen to identify specific and general inhibitors of protein nuclear import, from which ivermectin was identified as a potential inhibitor of importin α/β-mediated transport. In the present study, we characterized in detail the nuclear transport inhibitory properties of ivermectin, demonstrating that it is a broad-spectrum inhibitor of importin α/β nuclear import, with no effect on a range of other nuclear import pathways, including that mediated by importin β1 alone. Importantly, we establish for the first time that ivermectin has potent antiviral activity towards both HIV-1 and dengue virus, both of which are strongly reliant on importin α/β nuclear import, with respect to the HIV-1 integrase and NS5 (non-structural protein 5) polymerase proteins respectively. Ivermectin would appear to be an invaluable tool for the study of protein nuclear import, as well as the basis for future development of antiviral agents.
authors.affiliation: Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Wagstaff
authors.forename: Haran
authors.initials: H
authors.lastname: Sivakumaran
authors.forename: Steven M
authors.initials: SM
authors.lastname: Heaton
authors.forename: David
authors.initials: D
authors.lastname: Harrich
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
mesh_terms: D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D028884:Karyopherins; D007559:Ivermectin