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Article: Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle
Title | Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle |
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Authors | |
Keywords | influenza nucleoprotein small-molecule inhibitor |
Issue Date | 2021 |
Publisher | American Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/ |
Citation | Journal of Virology, 2021, v. 95 n. 9, p. article no. e01432-20 How to Cite? |
Abstract | Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization. |
Description | Hybrid open access |
Persistent Identifier | http://hdl.handle.net/10722/299294 |
ISSN | 2023 Impact Factor: 4.0 2023 SCImago Journal Rankings: 1.378 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Yang, F | - |
dc.contributor.author | Pang, B | - |
dc.contributor.author | Lai, KK | - |
dc.contributor.author | Cheung, NN | - |
dc.contributor.author | Dai, J | - |
dc.contributor.author | Zhang, W | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Chan, KH | - |
dc.contributor.author | Chen, H | - |
dc.contributor.author | Sze, KH | - |
dc.contributor.author | Zhang, H | - |
dc.contributor.author | Hao, Q | - |
dc.contributor.author | Yang, D | - |
dc.contributor.author | Yuen, KY | - |
dc.contributor.author | Kao, RY | - |
dc.date.accessioned | 2021-05-10T06:59:46Z | - |
dc.date.available | 2021-05-10T06:59:46Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Journal of Virology, 2021, v. 95 n. 9, p. article no. e01432-20 | - |
dc.identifier.issn | 0022-538X | - |
dc.identifier.uri | http://hdl.handle.net/10722/299294 | - |
dc.description | Hybrid open access | - |
dc.description.abstract | Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization. | - |
dc.language | eng | - |
dc.publisher | American Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/ | - |
dc.relation.ispartof | Journal of Virology | - |
dc.rights | Journal of Virology. Copyright © American Society for Microbiology. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | influenza | - |
dc.subject | nucleoprotein | - |
dc.subject | small-molecule inhibitor | - |
dc.title | Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle | - |
dc.type | Article | - |
dc.identifier.email | Chan, KH: chankh2@hkucc.hku.hk | - |
dc.identifier.email | Chen, H: hlchen@hku.hk | - |
dc.identifier.email | Sze, KH: khsze@hku.hk | - |
dc.identifier.email | Hao, Q: qhao@hku.hk | - |
dc.identifier.email | Yang, D: yangdan@hku.hk | - |
dc.identifier.email | Yuen, KY: kyyuen@hkucc.hku.hk | - |
dc.identifier.email | Kao, RY: rytkao@hkucc.hku.hk | - |
dc.identifier.authority | Chan, KH=rp01921 | - |
dc.identifier.authority | Chen, H=rp00383 | - |
dc.identifier.authority | Sze, KH=rp00785 | - |
dc.identifier.authority | Hao, Q=rp01332 | - |
dc.identifier.authority | Yang, D=rp00825 | - |
dc.identifier.authority | Yuen, KY=rp00366 | - |
dc.identifier.authority | Kao, RY=rp00481 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1128/JVI.01432-20 | - |
dc.identifier.pmid | 33627391 | - |
dc.identifier.pmcid | PMC8104107 | - |
dc.identifier.scopus | eid_2-s2.0-85104276049 | - |
dc.identifier.hkuros | 322422 | - |
dc.identifier.volume | 95 | - |
dc.identifier.issue | 9 | - |
dc.identifier.spage | article no. e01432 | - |
dc.identifier.epage | 20 | - |
dc.identifier.isi | WOS:000640382100013 | - |
dc.publisher.place | United States | - |