The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer.

@article{Yang2020TheBS,
  title={The broad spectrum antiviral ivermectin targets the host nuclear transport importin $\alpha$/$\beta$1 heterodimer.},
  author={Sundy N. Y. Yang and Sarah C Atkinson and Chunxiao Wang and Alexander Lee and Marie A. Bogoyevitch and Natalie A. Borg and David Andrew Jans},
  journal={Antiviral research},
  year={2020},
  pages={
          104760
        }
}
Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and Influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response. We previously identified the small molecule ivermectin as an inhibitor of HIV-1… Expand
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References

SHOWING 1-10 OF 87 REFERENCES
Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer
TLDR
GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity. Expand
Nucleocytoplasmic Trafficking of Dengue Non-structural Protein 5 as a Target for Antivirals.
TLDR
DENV non-structural protein 5 (NS5) traffics into and out of the host cell nucleus/nucleolus, being observed in the nucleus, although to differing extents, very early in infection in the case of all 4 DENV serotypes; with results from both reverse genetics and inhibitor studies indicating that this trafficking is critical to DENV infection. Expand
Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus
TLDR
It is established 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. Expand
Nuclear trafficking of proteins from RNA viruses: potential target for antivirals?
TLDR
The results validate nuclear protein import as an antiviral target, and suggest the identification and development of nuclear transport inhibitors as a viable therapeutic approach for a range of human and zoonotic pathogenic viruses. Expand
Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V
TLDR
It is shown that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents are considered. Expand
A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection.
TLDR
4-HPR is a novel antiviral that modulates the unfolded protein response, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model. Expand
Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication.
TLDR
It is confirmed that VEEV uses host importins and exportins during part of its life cycle and suggests that temporarily targeting host proteins that are hijacked for use by viruses is a viable antiviral therapy. Expand
Molecular dissection of an inhibitor targeting the HIV integrase dependent preintegration complex nuclear import
TLDR
Significantly, budesonide or its analogue flunisolide were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2‐LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. Expand
Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin.
TLDR
The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/β in vitro, and protected against infection from DENV1-4, and has potential in the clinical setting as a dengue antiviral. Expand
Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection.
TLDR
It is shown here for the first time that ZIKV NS5 is recognized with high nanomolar affinity by the host cell importin α/β1 heterodimer, and that this interaction can be blocked by the novel DENVNS5 targeting inhibitor N-(4-hydroxyphenyl) retinamide (4-HPR). Expand
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