Article thumbnail

The Kinase Inhibitor SFV785 Dislocates Dengue Virus Envelope Protein from the Replication Complex and Blocks Virus Assembly

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

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3157368
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2001). A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.
  2. (2006). A stem-loop-mediated reverse transcription real-time PCR for the selective detection and quantification of the replicative strand of an RNA virus.
  3. (2007). c-Src protein kinase inhibitors block assembly and maturation of dengue virus.
  4. (2008). Cell biology of lipid droplets.
  5. (2008). Cellular proteins in influenza virus particles.
  6. (1998). Characterization of a nerve growth factorinducible cellular activity that enhances herpes simplex virus type 1 gene expression and replication of an ICP0 null mutant in cells of neural lineage.
  7. (2009). Composition and three-dimensional architecture of the dengue virus replication and assembly sites.
  8. (2009). Dengue virus capsid protein usurps lipid droplets for viral particle formation.
  9. (2009). Dengue virus infection induces upregulation of GRP78, which acts to chaperone viral antigen production.
  10. (2005). Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell.
  11. (2009). Discovery of insect and human dengue virus host factors.
  12. (2007). Flaviviridae: The Viruses and Their Replication.
  13. (2005). Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection.
  14. (2006). Flavivirus induces interferon-beta gene expression through a pathway involving RIG-I-dependent IRF-3 and PI3Kdependent NF-kappaB activation.
  15. (2010). Further assembly required: construction and dynamics of the endoplasmic reticulum network.
  16. (2003). Garcia-Sastre A
  17. (1985). Growth, titration and purification of alphaviruses and flaviviruses. In:
  18. (2008). Hepatitis C virus core protein induces lipid droplet redistribution in a microtubule- and dynein-dependent manner.
  19. (2010). Inhibition of hepatitis C virus replication by a specific inhibitor of serinearginine-rich protein kinase.
  20. (2009). Initiation of hepatitis C virus infection requires the dynamic microtubule network: role of the viral nucleocapsid protein.
  21. (2009). Interaction of dengue virus envelope protein with endoplasmic reticulumresident chaperones facilitates dengue virus production.
  22. (2008). Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles.
  23. (2009). Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening.
  24. (2004). Markedly reduced severity of Dengue virus infection in mosquito cell cultures persistently infected with Aedes albopictus densovirus (AalDNV).
  25. (2009). Modification and reorganization of the cytoprotective cellular chaperone Hsp27 during herpes simplex virus type 1 infection.
  26. (1996). Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.
  27. (2002). Mycophenolic Acid inhibits dengue virus infection by preventing replication of viral RNA.
  28. (2005). Nuclear localization of Japanese encephalitis virus core protein enhances viral replication.
  29. (2011). Pediatric Dengue Vaccine Initiative, Global burden of dengue,
  30. (2007). Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication?
  31. (2009). PKA-induced F-actin rearrangement requires phosphorylation
  32. (1998). PRAK, a novel protein kinase regulated by the p38 MAP kinase.
  33. (2009). Progress towards a dengue vaccine.
  34. (2004). Proteomic approach identifies HSP27 as an interacting partner of the hepatitis C virus NS5A protein.
  35. (2006). Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking.
  36. RiceCM(2002) Highlypermissive celllines forsubgenomic and genomic hepatitis C virus RNA replication.
  37. (2008). RNA interference screen for human genes associated with West Nile virus infection.
  38. (2002). RNAi-mediated PTB depletion leads to enhanced exon definition.
  39. (2008). Structural and functional characterization of nonstructural protein 2 for its role in hepatitis C virus assembly.
  40. (2004). Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon- alpha.
  41. (2008). The capsid-coding region hairpin element (cHP) is a critical determinant of dengue virus and West Nile virus RNA synthesis.
  42. (2010). The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex.
  43. (2007). The lipid droplet is an important organelle for hepatitis C virus production.
  44. (2009). The polypyrimidine tract-binding protein is required for efficient dengue virus propagation and associates with the viral replication machinery.
  45. (2002). The roles of inflammation, STAT transcription factors, and nerve growth factor in viral reactivation and herpes keratitis.
  46. (2005). The Src family kinase c-Yes is required for maturation of West Nile virus particles.
  47. (2009). Trans-complementation of an NS2 defect in a late step in hepatitis C virus (HCV) particle assembly and maturation.
  48. (2007). Trksignaling endosomes are generated by Rac-dependent macroendocytosis.
  49. (2006). Utilization of host SR protein kinases and RNA-splicing machinery during viral replication.
  50. (2008). Virological characterization of the hepatitis C virus JFH-1 strain in lymphocytic cell lines.