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Antiviral Res
. 2024 Feb 11:105822.
doi: 10.1016/j.antiviral.2024.105822. Online ahead of print. Discovery of cyperenoic acid as a potent and novel entry inhibitor of influenza A virus
Xiaoli Zhang 1 , Yiping Xia 2 , Peibo Li 1 , Zhongnan Wu 2 , Ruilin Li 3 , Jialiao Cai 2 , Yubo Zhang 4 , Guocai Wang 2 , Yaolan Li 2 , Wei Tang 5 , Weiwei Su 6
Affiliations
Influenza therapeutics with new targets and modes of action are urgently needed due to the frequent emergence of mutants resistant to currently available anti-influenza drugs. Here we report the in vitro and in vivo anti-influenza A virus activities of cyperenoic acid, a natural compound, which was isolated from a Chinese medicine Croton crassifolius Geise. Cyperenoic acid could potently suppress H1N1, H3N2 and H9N2 virus replication with IC50 values ranging from 0.12 to 15.13 μM, and showed a low cytotoxicity against MDCK cells (CC50 = 939.2 ± 60.0 μM), with selectivity index (SI) values ranging from 62 to 7823.Oral or intraperitoneal treatment of cyperenoic acid effectively protected mice against a lethal influenza virus challenge, comparable to the efficacy of Tamiflu. Additionally, cyperenoic acid also significantly reduced lung virus titer and alleviated influenza-induced acute lung injury in infected mice. Mechanism-of-action studies revealed that cyperenoic acid exhibited its anti-influenza activity during the entry stage of viral replication by inhibiting HA-mediated viral fusion. Simulation docking analyses of cyperenoic acid with the HA structures implied that cyperenoic acid binds to the stalk domain of HA in a cavity near the fusion peptide. Collectively, these results demonstrate that cyperenoic acid is a promising lead compound for the anti-influenza drug development and this research provides a useful small-molecule probe for studying the HA-mediated viral entry process.
Keywords: Antivirals; Cyperenoic acid; Drug discovery; Entry inhibitor; Influenza virus.
. 2024 Feb 11:105822.
doi: 10.1016/j.antiviral.2024.105822. Online ahead of print. Discovery of cyperenoic acid as a potent and novel entry inhibitor of influenza A virus
Xiaoli Zhang 1 , Yiping Xia 2 , Peibo Li 1 , Zhongnan Wu 2 , Ruilin Li 3 , Jialiao Cai 2 , Yubo Zhang 4 , Guocai Wang 2 , Yaolan Li 2 , Wei Tang 5 , Weiwei Su 6
Affiliations
- PMID: 38350497
- DOI: 10.1016/j.antiviral.2024.105822
Influenza therapeutics with new targets and modes of action are urgently needed due to the frequent emergence of mutants resistant to currently available anti-influenza drugs. Here we report the in vitro and in vivo anti-influenza A virus activities of cyperenoic acid, a natural compound, which was isolated from a Chinese medicine Croton crassifolius Geise. Cyperenoic acid could potently suppress H1N1, H3N2 and H9N2 virus replication with IC50 values ranging from 0.12 to 15.13 μM, and showed a low cytotoxicity against MDCK cells (CC50 = 939.2 ± 60.0 μM), with selectivity index (SI) values ranging from 62 to 7823.Oral or intraperitoneal treatment of cyperenoic acid effectively protected mice against a lethal influenza virus challenge, comparable to the efficacy of Tamiflu. Additionally, cyperenoic acid also significantly reduced lung virus titer and alleviated influenza-induced acute lung injury in infected mice. Mechanism-of-action studies revealed that cyperenoic acid exhibited its anti-influenza activity during the entry stage of viral replication by inhibiting HA-mediated viral fusion. Simulation docking analyses of cyperenoic acid with the HA structures implied that cyperenoic acid binds to the stalk domain of HA in a cavity near the fusion peptide. Collectively, these results demonstrate that cyperenoic acid is a promising lead compound for the anti-influenza drug development and this research provides a useful small-molecule probe for studying the HA-mediated viral entry process.
Keywords: Antivirals; Cyperenoic acid; Drug discovery; Entry inhibitor; Influenza virus.