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

@article{Wagstaff2012IvermectinIA,
  title={Ivermectin is a specific inhibitor of importin $\alpha$/$\beta$-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus},
  author={Kylie M. Wagstaff and Haran Sivakumaran and Steven M Heaton and David Harrich and David Andrew Jans},
  journal={Biochemical Journal},
  year={2012},
  volume={443},
  pages={851 - 856}
}
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… Expand

Paper Mentions

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InterventionDrug, Other
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ConditionsCovid19
InterventionDrug
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ConditionsSARS-CoV-2 Infection
InterventionDrug
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ConditionsCOVID-19
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TLDR
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References

SHOWING 1-10 OF 52 REFERENCES
HIV-1 integrase is capable of targeting DNA to the nucleus via an Importin α/β-dependent mechanism
TLDR
In vitro techniques are utilized to assess the nuclear import properties of the HIV-1 enzyme IN, and it is shown that IN interacts with members of the Imp (Importin) family of nuclear transport proteins with high affinity and exhibits rapid nuclear accumulation within an in vitro assay, indicating that IN possesses potent nucleophilic potential. Expand
Nuclear Localization of Dengue Virus Nonstructural Protein 5 Through Its Importin α/β–Recognized Nuclear Localization Sequences is Integral to Viral Infection
TLDR
The results overall indicate that NS5 nuclear localization through the aNLS is integral to viral infection, with significant implications for other flaviviruses of medical importance, such as yellow fever and West Nile viruses. Expand
CRM1-mediated Nuclear Export of Dengue Virus RNA Polymerase NS5 Modulates Interleukin-8 Induction and Virus Production*
TLDR
This is the first report of a nuclear export sequence within NS5 for any member of the Flavivirus genus; because of its high conservation within the genus, it may represent a target for the treatment of diseases caused by several medically important flaviviruses. Expand
An AlphaScreen®-Based Assay for High-Throughput Screening for Specific Inhibitors of Nuclear Import
TLDR
A novel high-throughput screening assay for identifying inhibitors of nuclear import, particularly IN, based on amplified luminescent proximity homogeneous assay (AlphaScreen®) technology is described, which is high throughput, requires low amounts of material, and is efficient and cost-effective. Expand
Nuclear import of the respiratory syncytial virus matrix protein is mediated by importin beta1 independent of importin alpha.
TLDR
This is the first report of the importin binding and nuclear import properties of a gene product from a negative sense RNA virus, with implications for the function of RSV M and possibly other viral M proteins in the nucleus of infected cells. Expand
A peptide inhibitor of exportin1 blocks shuttling of the adenoviral E1B 55 kDa protein but not export of viral late mRNAs.
TLDR
It is established that viral late mRNAs are not exported by exportin1, as well as the value of peptide inhibitors in investigation of mRNA export regulation in adenovirus-infected cells. Expand
Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport.
TLDR
A microtiter plate based permeabilized cell screen for small molecule inhibitors of the importin α/β pathway is devised and β-turn and α-helix peptidomimetic compounds that selectively inhibit nuclear import by importinα/β but not by transportin are identified. Expand
The Arginine-Rich Domains Present in Human Immunodeficiency Virus Type 1 Tat and Rev Function as Direct Importin β-Dependent Nuclear Localization Signals
TLDR
A novel class of arginine-rich NLS sequences that are direct targets for Imp β and that therefore function independently of Imp α is defined, which may in part explain why the interaction of the Rev nuclear RNA export factor with target RNA species is efficient in the cell nucleus yet is released in the cytoplasm. Expand
Identification of a small molecule inhibitor of importin β mediated nuclear import by confocal on-bead screening of tagged one-bead one-compound libraries.
TLDR
Karyostatin 1A binds importin β with high nanomolar affinity and specifically inhibits importin α/β mediated nuclear import at low micromolar concentrations in vitro and in living cells, without perturbing transportin mediatednuclear import or CRM1 mediated nuclear export. Expand
The HIV-1 Tat Nuclear Localization Sequence Confers Novel Nuclear Import Properties*
TLDR
Results demonstrate that, dependent on ATP for release from cytoplasmic retention, the Tat-NLS is able to confer nuclear entry and binding to nuclear components, and indicate that Tat accumulates in the nucleus through a novel import pathway. Expand
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