• myGriffith
    • Staff portal
    • Contact Us⌄
      • Future student enquiries 1800 677 728
      • Current student enquiries 1800 154 055
      • International enquiries +61 7 3735 6425
      • General enquiries 07 3735 7111
      • Online enquiries
      • Staff phonebook
    View Item 
    •   Home
    • Griffith Research Online
    • Journal articles
    • View Item
    • Home
    • Griffith Research Online
    • Journal articles
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

  • All of Griffith Research Online
    • Communities & Collections
    • Authors
    • By Issue Date
    • Titles
  • This Collection
    • Authors
    • By Issue Date
    • Titles
  • Statistics

  • Most Popular Items
  • Statistics by Country
  • Most Popular Authors
  • Support

  • Contact us
  • FAQs
  • Admin login

  • Login
  • Luteolin escape mutants of dengue virus map to prM and NS2B and reveal viral plasticity during maturation

    Author(s)
    Peng, Minhua
    Swarbrick, Crystall Marie Dawn
    Chan, Kitti Wing-Ki
    Luo, Dahai
    Zhang, Wei
    Lai, Xiaoping
    Li, Geng
    Vasudevan, Subhash G
    Griffith University Author(s)
    Swarbrick, Crystall
    Year published
    2018
    Metadata
    Show full item record
    Abstract
    We previously showed that luteolin, a well-known plant-derived component found in the “heat clearing” class of Traditional Chinese Medicine (TCM) herbs, is an uncompetitive inhibitor (Ki 58.6 μM) of the host proprotein convertase furin, an endoprotease that is required for maturation of flaviviruses in the trans-Golgi compartment. Luteolin also weakly inhibited recombinant dengue virus NS2B/NS3 protease (Ki 140.36 μM) non-competitively. In order to further explore the mechanism of inhibition we isolated resistant mutants by continuous passaging of DENV2 in the presence of increasing concentrations of luteolin. Nucleotide ...
    View more >
    We previously showed that luteolin, a well-known plant-derived component found in the “heat clearing” class of Traditional Chinese Medicine (TCM) herbs, is an uncompetitive inhibitor (Ki 58.6 μM) of the host proprotein convertase furin, an endoprotease that is required for maturation of flaviviruses in the trans-Golgi compartment. Luteolin also weakly inhibited recombinant dengue virus NS2B/NS3 protease (Ki 140.36 μM) non-competitively. In order to further explore the mechanism of inhibition we isolated resistant mutants by continuous passaging of DENV2 in the presence of increasing concentrations of luteolin. Nucleotide sequence analysis of the luteolin-resistant escape mutants revealed nucleotide changes that lead to amino acid substitutions in the prM (T79R) and NS2B (I114M) genes. These mutations were introduced into a DENV2 infectious clone and tested for replication in Huh-7 cells. Interestingly we found that the replication kinetics of prM T19R-NS2B I114M double-mutant (DM) was similar to wild-type virus (WT). On the other hand the prM T79R single mutant (SM1) was attenuated and the NS2B I114M single mutant (SM2) showed enhanced replication. Time of drug addition assay with luteolin showed that the mutant viruses were able to produce more mature virions than WT in the order DM > SM2>SM1>WT. Exogenous addition of furin to purified immature WT or mutant viruses revealed that luteolin blocked the prM cleavage of WT and SM2 at a similar level. On the other hand the SM1 immature virus showed some cleavage while the DM immature virus revealed efficient furin cleavage of prM even in the presence of 50 μM luteolin. Our findings suggest that luteolin inhibition of furin may occur at host/pathogen interface that permits the virus to escape the suppression by mutating key residue that may lead to an altered interface.
    View less >
    Journal Title
    Antiviral Research
    Volume
    154
    DOI
    https://doi.org/10.1016/j.antiviral.2018.04.013
    Subject
    Microbiology
    Medical microbiology
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/384617
    Collection
    • Journal articles

    Footer

    Disclaimer

    • Privacy policy
    • Copyright matters
    • CRICOS Provider - 00233E
    • TEQSA: PRV12076

    Tagline

    • Gold Coast
    • Logan
    • Brisbane - Queensland, Australia
    First Peoples of Australia
    • Aboriginal
    • Torres Strait Islander