Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Abstract

<jats:p>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.</jats:p>

Influence of importin α/β and exportin 1 on equine herpesvirus type 1 (EHV-1) replication in primary murine neurons

“…1 C-D), thus it can be assumed that EHV-1 was not dependent on the exportin 1-mediated nuclear export. Many studies have previously confirmed that ivermectin is able to inhibit replication of HIV-1, dengue virus and West Nile virus (Mastrangelo et al 2012, Wagstaff et al 2012. It has been demonstrated that ivermectin is affecting NS3 helicase activity, required during viral RNA replication.…”

“…Receptor-mediated nuclear import and export is utilized by adenoviruses, parvoviruses, flaviviruses, retroviruses and herpesviruses and disruption of specific nuclear transport pathways is crucial for the efficacious replication cycle (Greber and Correspondence to: A. Słońska, e-mail: anex007@op.pl, tel. : 22 593 60 55 Fornerod, 2004, Mastrangelo et al 2012, Wagstaff et al 2012. In the present study, we have used two inhibitors -ivermectin as an importin α/β inhibitor and leptomycin B as an exportin 1 inhibitor to determine their effect on EHV-1 replication in primary murine neurons.…”

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

“…Next, we searched clinically available drugs that can potentially target KPNB1 and found a recent report that ivermectin, an FDA-approved antiparasitic drug, inhibits importin α/β-mediated nuclear import (25). In our initial studies, we found that ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig.…”

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

“…In mammalian cells, high concentrations of ivermectin not only activate chloride channels but also induce reactive oxygen species accumulation, block the β-catenin pathway, and inhibit the tumor-suppressive activity of PAK kinase (49)(50)(51)(52). In addition, in virus-infected cells, ivermectin impairs the nuclear import of signaling molecules mediated by α/β importins (53). This inhibition of nuclear import may not only prevent nuclear localization and activation of YAP1 but perhaps also that of other targets that could contribute to hepatocarcinogenesis.…”