The kinase inhibitor sfv785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly

Azlinda Anwar, Takamitsu Hosoya, Kok Mun Leong, Hiroshi Onogi, Yukiko Okuno, Toshiyuki Hiramatsu, Hiroko Koyama, Masaaki Suzuki, Masatoshi Hagiwara, Mariano Garcia-Blanco

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.

Original languageEnglish (US)
Article numbere23246
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - 2011
Externally publishedYes

Fingerprint

Viral Envelope Proteins
Virus Assembly
Dengue virus
Dengue Virus
Viruses
phosphotransferases (kinases)
Phosphotransferases
virion
Virion
proteins
Nucleocapsid
nucleocapsid
Dengue
RNA
1-(2-(1-azacyclooctanyl)-5-(trifluoromethyl))phenyl-3-nicotinoylthiourea
virus assembly
Yellow fever virus
antiviral agents
hepatitis C
synthesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The kinase inhibitor sfv785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly. / Anwar, Azlinda; Hosoya, Takamitsu; Leong, Kok Mun; Onogi, Hiroshi; Okuno, Yukiko; Hiramatsu, Toshiyuki; Koyama, Hiroko; Suzuki, Masaaki; Hagiwara, Masatoshi; Garcia-Blanco, Mariano.

In: PLoS One, Vol. 6, No. 8, e23246, 2011.

Research output: Contribution to journalArticle

Anwar, A, Hosoya, T, Leong, KM, Onogi, H, Okuno, Y, Hiramatsu, T, Koyama, H, Suzuki, M, Hagiwara, M & Garcia-Blanco, M 2011, 'The kinase inhibitor sfv785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly', PLoS One, vol. 6, no. 8, e23246. https://doi.org/10.1371/journal.pone.0023246
Anwar, Azlinda ; Hosoya, Takamitsu ; Leong, Kok Mun ; Onogi, Hiroshi ; Okuno, Yukiko ; Hiramatsu, Toshiyuki ; Koyama, Hiroko ; Suzuki, Masaaki ; Hagiwara, Masatoshi ; Garcia-Blanco, Mariano. / The kinase inhibitor sfv785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly. In: PLoS One. 2011 ; Vol. 6, No. 8.
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