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Conference Paper: A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication
Title | A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication |
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Authors | |
Issue Date | 2016 |
Publisher | International Society for Influenza and Other Respiratory Virus Diseases. |
Citation | The 9th International Scientific Conference of Options for the Control of Influenza (Options-9), Chicago, IL., 24-28 August 2016. In Conference Program, 2016, p. 315, abstract no. LBP-2 How to Cite? |
Abstract | BACKGROUND: The conserved residues 318−483 in PB2 subunit of influenza
A polymerase is an independently folded cap-binding domain (PB2cap)
that exhibits a distinct binding mode from other host cap-binding proteins,
which suggests that PB2cap might be an ideal drug target. This study aims to
identify a new class of anti-influenza inhibitors that specifically disrupts the
interaction between PB2cap and host cap-structures.
METHOD: An innovative fluorescence polarization assay was established
for primary screening, followed by cap-binding inhibitory activity, antiviral
efficacy and cytotoxicity evaluations of the selected compounds. The best
compound was characterized by multi-cycle virus growth assay, crossprotection
test, synergism evaluation, mini-replicon assay, binding affinity
analysis, docking simulation and mouse study.
RESULTS: Several PB2 cap-binding inhibitors were discovered. One of the
best compounds, designated PB2-39, was identified as a potent inhibitor
against the replication of multiple subtypes of influenza A virus, including
H1N1, H3N2, H5N1, H7N7, H7N9, H9N2 in vitro and H1N1, H5N1, H7N9 in vivo.
Combinational treatment of the influenza virus release inhibitor zanamivir
and PB2-39 exerted synergistic anti-influenza effect. Mechanistic experiments
supported that PB2-39 suppressed viral polymerase activity. Docking and
binding affinity analyses demonstrated that PB2-39 interacted with the PB2
cap-binding pocket, suggesting its role as a cap-binding competitor.
CONCLUSION: Our study provides new insights for the development of
influenza PB2 cap-binding inhibitors through reverse chemical genetics. To
the best of our knowledge, this is the first biochemical screening system that
utilizes PB2 cap-binding domain as a selection target. |
Description | Late Breaking Poster Abstracts: no. LBP-2 |
Persistent Identifier | http://hdl.handle.net/10722/232503 |
DC Field | Value | Language |
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dc.contributor.author | Yuan, S | - |
dc.contributor.author | Zheng, B | - |
dc.date.accessioned | 2016-09-20T05:30:28Z | - |
dc.date.available | 2016-09-20T05:30:28Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | The 9th International Scientific Conference of Options for the Control of Influenza (Options-9), Chicago, IL., 24-28 August 2016. In Conference Program, 2016, p. 315, abstract no. LBP-2 | - |
dc.identifier.uri | http://hdl.handle.net/10722/232503 | - |
dc.description | Late Breaking Poster Abstracts: no. LBP-2 | - |
dc.description.abstract | BACKGROUND: The conserved residues 318−483 in PB2 subunit of influenza A polymerase is an independently folded cap-binding domain (PB2cap) that exhibits a distinct binding mode from other host cap-binding proteins, which suggests that PB2cap might be an ideal drug target. This study aims to identify a new class of anti-influenza inhibitors that specifically disrupts the interaction between PB2cap and host cap-structures. METHOD: An innovative fluorescence polarization assay was established for primary screening, followed by cap-binding inhibitory activity, antiviral efficacy and cytotoxicity evaluations of the selected compounds. The best compound was characterized by multi-cycle virus growth assay, crossprotection test, synergism evaluation, mini-replicon assay, binding affinity analysis, docking simulation and mouse study. RESULTS: Several PB2 cap-binding inhibitors were discovered. One of the best compounds, designated PB2-39, was identified as a potent inhibitor against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9, H9N2 in vitro and H1N1, H5N1, H7N9 in vivo. Combinational treatment of the influenza virus release inhibitor zanamivir and PB2-39 exerted synergistic anti-influenza effect. Mechanistic experiments supported that PB2-39 suppressed viral polymerase activity. Docking and binding affinity analyses demonstrated that PB2-39 interacted with the PB2 cap-binding pocket, suggesting its role as a cap-binding competitor. CONCLUSION: Our study provides new insights for the development of influenza PB2 cap-binding inhibitors through reverse chemical genetics. To the best of our knowledge, this is the first biochemical screening system that utilizes PB2 cap-binding domain as a selection target. | - |
dc.language | eng | - |
dc.publisher | International Society for Influenza and Other Respiratory Virus Diseases. | - |
dc.relation.ispartof | International Scientific Conference of Options for the Control of Influenza, Options-9 | - |
dc.title | A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Yuan, S: yuansf@hku.hk | - |
dc.identifier.email | Zheng, B: bzheng@hkucc.hku.hk | - |
dc.identifier.authority | Zheng, B=rp00353 | - |
dc.identifier.hkuros | 264779 | - |
dc.identifier.spage | 315, abstract no. LBP-2 | - |
dc.identifier.epage | 315, abstract no. LBP-2 | - |
dc.publisher.place | United States | - |