Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase
Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcriptio...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00178/full |
| _version_ | 1818015039806767104 |
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| author | Ao Hu Ao Hu Jing Li Wei Tang Ge Liu Ge Liu Haiwei Zhang Chunlan Liu Xulin Chen Xulin Chen Xulin Chen |
| author_facet | Ao Hu Ao Hu Jing Li Wei Tang Ge Liu Ge Liu Haiwei Zhang Chunlan Liu Xulin Chen Xulin Chen Xulin Chen |
| author_sort | Ao Hu |
| collection | DOAJ |
| description | Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the cap-snatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection in vitro and in vivo. Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs. |
| first_indexed | 2024-04-14T06:51:55Z |
| format | Article |
| id | doaj.art-f0b3a01d5e8846bea78600b8989c753d |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-14T06:51:55Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-f0b3a01d5e8846bea78600b8989c753d2022-12-22T02:07:00ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-02-011110.3389/fmicb.2020.00178515644Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA PolymeraseAo Hu0Ao Hu1Jing Li2Wei Tang3Ge Liu4Ge Liu5Haiwei Zhang6Chunlan Liu7Xulin Chen8Xulin Chen9Xulin Chen10State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaInfluenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the cap-snatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection in vitro and in vivo. Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs.https://www.frontiersin.org/article/10.3389/fmicb.2020.00178/fullinfluenzacap snatchingvRdRpanthralincap-bindingendonuclease |
| spellingShingle | Ao Hu Ao Hu Jing Li Wei Tang Ge Liu Ge Liu Haiwei Zhang Chunlan Liu Xulin Chen Xulin Chen Xulin Chen Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase Frontiers in Microbiology influenza cap snatching vRdRp anthralin cap-binding endonuclease |
| title | Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase |
| title_full | Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase |
| title_fullStr | Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase |
| title_full_unstemmed | Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase |
| title_short | Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase |
| title_sort | anthralin suppresses the proliferation of influenza virus by inhibiting the cap binding and endonuclease activity of viral rna polymerase |
| topic | influenza cap snatching vRdRp anthralin cap-binding endonuclease |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00178/full |
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