Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection.

Abstract

In the absence of approved therapeutics, Zika virus (ZIKV)'s recent prolific outbreaks in the Americas, together with impacts on unborn fetuses of infected mothers, make it a pressing human health concern worldwide. Although a key player in viral replication in the infected host cell cytoplasm, ZIKV non-structural protein 5 (NS5) appears to contribute integrally to pathogenesis by localising in the host cell nucleus, in similar fashion to NS5 from Dengue virus (DENV). We show 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 DENV NS5 targeting inhibitor N-(4-hydroxyphenyl) retinamide (4-HPR). Importantly, we show that 4-HPR has potent anti-ZIKV activity at low μM concentrations. With an established safety profile for human use, 4-HPR represents an exciting possibility as an anti-ZIKV agent.

• Authors: Chunxiao Wang, Sundy N Y Yang, Kate Smith, Jade K Forwood, David A Jans
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 493 Issue 4 Pg. 1555-1559 (12 02 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28988109 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• NS5 protein, dengue virus
• Viral Nonstructural Proteins
• alpha Karyopherins
• beta Karyopherins
• Fenretinide

Topics

• Active Transport, Cell Nucleus (drug effects, physiology)
• Amino Acid Sequence
• Animals
• Antiviral Agents (pharmacology)
• Chlorocebus aethiops
• Conserved Sequence
• Fenretinide (pharmacology)
• Humans
• Vero Cells
• Viral Nonstructural Proteins (antagonists & inhibitors, genetics, physiology)
• Virus Replication (drug effects)
• Zika Virus (drug effects, genetics, physiology)
• Zika Virus Infection (drug therapy, prevention & control, virology)
• alpha Karyopherins (physiology)
• beta Karyopherins (physiology)