tetano
Editor, Senior Moderator
J Cell Mol Med. 2017 Nov 30. doi: 10.1111/jcmm.13467. [Epub ahead of print]
[h=1]Identification of a novel compound targeting the nuclear export of influenza A virus nucleoprotein.[/h] Huang F[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Chen J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Zhang J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Tan L[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Lu G[SUP]5[/SUP], Luo Y[SUP]5[/SUP], Pan T[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Liang J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Li Q[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Luo B[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Zhang H[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Lu G[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug-resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti-influenza compound, ZBMD-1, from a library of 20,000 compounds using cell-based influenza A infection assays. We found that ZBMD-1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC[SUB]50[/SUB] ranging from 0.41-1.14 μM. Furthermore, ZBMD-1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD-1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD-1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro-inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD-1 is a promising anti-influenza compound which can be further investigated as a useful strategy against IAVs in the future.
[h=4]KEYWORDS:[/h] compound ZBMD-1; influenza A virus; nuclear export; nucleoprotein
PMID: 29193684 DOI: 10.1111/jcmm.13467
[h=1]Identification of a novel compound targeting the nuclear export of influenza A virus nucleoprotein.[/h] Huang F[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Chen J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Zhang J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Tan L[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Lu G[SUP]5[/SUP], Luo Y[SUP]5[/SUP], Pan T[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Liang J[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Li Q[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Luo B[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Zhang H[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Lu G[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug-resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti-influenza compound, ZBMD-1, from a library of 20,000 compounds using cell-based influenza A infection assays. We found that ZBMD-1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC[SUB]50[/SUB] ranging from 0.41-1.14 μM. Furthermore, ZBMD-1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD-1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD-1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro-inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD-1 is a promising anti-influenza compound which can be further investigated as a useful strategy against IAVs in the future.
[h=4]KEYWORDS:[/h] compound ZBMD-1; influenza A virus; nuclear export; nucleoprotein
PMID: 29193684 DOI: 10.1111/jcmm.13467