Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response.
Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases.
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Lin-Lin
LL
Ma
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Hui-Qiang
HQ
Wang
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Ping
P
Wu
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Jin
J
Hu
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Jin-Qiu
JQ
Yin
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Shuo
S
Wu
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Miao
M
Ge
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Wen-Fang
WF
Sun
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Xinjiang 830011, China.
Jiang-Yu
JY
Zhao
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Xinjiang 830011, China.
Haji Akber
HA
Aisa
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: yuhuanlibj@126.com.
Yu-Huan
YH
Li
Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: Jiang.jdong@163.com.
Jian-Dong
JD
Jiang
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D052176:Azulenes / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D007189:Indans / Q000008:administration & dosage*; D009980:Influenza A virus / Q000187:drug effects / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D007372:Interferons / Q000008:administration & dosage; D007555:Isoxazoles / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D012717:Sesquiterpenes / Q000008:administration & dosage*; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
D000998:Antiviral Agents; D052176:Azulenes; D007189:Indans; D007555:Isoxazoles; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012717:Sesquiterpenes; C000625673:YZH-106; C057488:rupestonic acid; D007372:Interferons; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
Heme oxygenase-1; Influenza virus; Rupestonic acid derivative; Type I interferon