1.A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo.
Daming ZUO ; Yu CHEN ; Jian-Piao CAI ; Hao-Yang YUAN ; Jun-Qi WU ; Yue YIN ; Jing-Wen XIE ; Jing-Min LIN ; Jia LUO ; Yang FENG ; Long-Jiao GE ; Jia ZHOU ; Ronald J QUINN ; San-Jun ZHAO ; Xing TONG ; Dong-Yan JIN ; Shuofeng YUAN ; Shao-Xing DAI ; Min XU
Protein & Cell 2023;14(1):37-50
The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
Animals
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Mice
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Antiviral Agents/pharmacology*
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COVID-19
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Hepatitis B virus
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Interferon Type I/metabolism*
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SARS-CoV-2/drug effects*
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B/antagonists & inhibitors*
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