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  • Title: Small molecule inhibitors possibly targeting the rearrangement of Zika virus envelope protein.
    Author: Sharma N, Prosser O, Kumar P, Tuplin A, Giri R.
    Journal: Antiviral Res; 2020 Oct; 182():104876. PubMed ID: 32783901.
    Abstract:
    The recurrent public health threat imposed by Zika Virus (ZIKV) in various geographical areas necessitates the immediate development of antiviral compounds or vaccines. Flaviviral Envelope (E) proteins are essential for host-cell recognition and virion entry. Consequently, they represent an important target for antiviral therapy, with the aim of preventing viral spread during early stages of infection. Due to conformational rearrangement during entry, flavivirus E proteins present several alternative conformations as potential antiviral targets - for blocking entry or virus-host membrane fusion. We previously identified a conserved hydrophobic region, between DI/DIII of ZIKV E protein, with potential to act as an antiviral target. Here, we screened commercially available antiviral compound libraries against ZIKV E protein, using a structure-based drug discovery approach. The antiviral efficacy of the top ten screened compounds were experimentally validated for inhibition of ZIKV replication in Vero Cells. Compound F1065-0358 was observed to inhibit ZIKV replication with an IC50 of 14.0 μM. Ligand-protein complex molecular dynamic simulations confirmed the stability of ligand binding up to 100 ns. Together, results from this study indicate that F1065-0358 functions as a ZIKV virus inhibitor by interfering E protein conformational rearrangement. Furthermore, given that F1065-0358 interacts with highly conserved residues of E protein, this raises the potential for its efficacy against other pathogenic flaviviruses.
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