Nucleocytoplasmic trafficking of dengue non-structural protein 5 as a target for antivirals

David A. Jans, Alexander J. Martin

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

3 Citations (Scopus)

Abstract

Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in infected cells, including RNA viruses such as the flavivirus Dengue virus (DENV). 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. Knowledge of the transporters and targeting signals responsible for nuclear trafficking of NS5 has enabled inhibitors of DENV NS5 nuclear import to be identified using a novel screening/counterscreen approach. N-(4-hydroxyphenyl) retinamide (4-HPR) is of particular interest as a specific, non-toxic inhibitor able to protect against infection by all four serotypes of DENV, as well as the severe, antibody-enhanced form of DENV infection, in a lethal mouse model. Since 4-HPR can also inhibit DENV-related flaviviruses of medical significance such as West Nile Virus and Zika virus, it is of great interest for future commercialisation. Targeting nucleocytoplasmic trafficking of flavivirus proteins promises to be a powerful strategy to counter flaviviruses, for which the development of protective vaccines has thus far proven problematic.

Original languageEnglish
Title of host publicationDengue and Zika
Subtitle of host publicationControl and Antiviral Treatment Strategies
EditorsRolf Hilgenfeld, Subhash G. Vasudevan
Place of PublicationSingapore
PublisherSpringer
Pages199-213
Number of pages15
ISBN (Electronic)9789811087271
ISBN (Print)9789811087264
DOIs
Publication statusPublished - 1 Jan 2018

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1062
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • 4-HPR
  • Antiviral
  • Dengue virus
  • DENV
  • Nuclear trafficking
  • Nucleocytoplasmic trafficking
  • Nucleus

Cite this

Jans, D. A., & Martin, A. J. (2018). Nucleocytoplasmic trafficking of dengue non-structural protein 5 as a target for antivirals. In R. Hilgenfeld, & S. G. Vasudevan (Eds.), Dengue and Zika: Control and Antiviral Treatment Strategies (pp. 199-213). (Advances in Experimental Medicine and Biology; Vol. 1062). Springer. https://doi.org/10.1007/978-981-10-8727-1_15