Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport

Ambrus, Géza; Whitby, Landon R.; Singer, Eric L; Trott, Oleg; Choi, Eun‐A; Olson, Arthur J.; Boger, Dale L.; Gerace, Larry

doi:10.1016/j.bmc.2010.08.038

Cited by 25 publications

(19 citation statements)

References 52 publications

(44 reference statements)

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“…LMB interacts specifically with a cysteine residue in CRM1 thereby inhibiting binding between the nuclear export receptor and its cargo proteins (Kudo et al, 1999). Although other inhibiting compounds such as ratjadones or several small-molecule inhibitors have been suggested, these have not been extensively tested (Koster et al, 2003;Ambrus et al, 2010;Hintersteiner et al, 2010). Recently, Wagstaff and colleagues identified the chemical Ivermectin (IVM) as a specific inhibitor of nuclear import (Wagstaff et al, 2011(Wagstaff et al, , 2012.…”

Section: Introductionmentioning

confidence: 96%

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

Kosyna

Nagel²,

Kluxen

et al. 2015

Biological Chemistry

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Hypoxia-inducible transcription factors (HIFs) regulate hundreds of genes involved in cellular adaptation to reduced oxygen availability. HIFs consist of an O2-labile α-subunit (primarily HIF-1α and HIF-2α) and a constitutive HIF-1β subunit. In normoxia the HIF-α subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1-3, resulting in recognition by von Hippel-Lindau protein, ubiquitination and proteasomal degradation. In contrast, reduced oxygen availability inhibits PHD activity resulting in HIF-1α stabilisation and nuclear accumulation. Nuclear import of HIF-1α mainly depends on classical nuclear localisation signals (NLS) and involves importin α/β heterodimers. Recently, a specific inhibitor of nuclear import has been identified that inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family. In this study we evaluated the physiological activity of this importin α/β-inhibitor (Ivermectin) in the hypoxia response pathway. Treatment with Ivermectin decreases binding activity of HIF-1α to the importin α/β-heterodimer. Moreover, HIF-1α nuclear localisation, nuclear HIF-1α protein levels, HIF-target gene expression, as well as HIF-transcriptional activity are reduced upon Ivermectin treatment. For the first time, we demonstrate the effect of specific importin α/β-inhibition on the hypoxic response on the molecular level.

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Section: Introductionmentioning

confidence: 96%

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

Kosyna

Nagel²,

Kluxen

et al. 2015

Biological Chemistry

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“…Although other inhibitory compounds are beginning to be developed [8–16], including compounds that are structurally related to LMB such as ratjadone, peptide-based inhibitors and several small-molecule inhibitors [17–21], these are not widely available and have not been extensively tested. Clearly, there is an urgent need for new and specific inhibitors of components of the mammalian cell nuclear transport machinery.…”

Section: Introductionmentioning

confidence: 99%

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

Wagstaff

Sivakumaran

Heaton

et al. 2012

Biochemical Journal

638

615

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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.

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“…Recently, a few inhibitors of nuclear import have been described but none have been tested for specificity, nor have they been tested for their anticancer effects. Small molecule peptidomimetic inhibitors of Kpna/b-mediated transport were identified in an in vitro screen; however, these inhibitors have low potency and are not cell permeable, hence no inhibition of Kpna/b-mediated nuclear import could be observed in vivo (12). Peptide inhibitors that bind Kpna with a strong affinity have also been described, yet these do not inhibit Kpnb1 directly (13).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

Watt

Chi

Stelma

et al. 2016

Molecular Cancer Therapeutics

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Karyopherin beta 1 (Kpnb1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnb1 expression was found in certain cancers and Kpnb1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnb1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnb1 and Inhibitor of Nuclear Import-43, INI-43

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Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport

Cited by 25 publications

References 52 publications

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

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

Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

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