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....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.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.31960093,81973210,81873872,82071781,32160153)the Natural Science Foundation of Yunnan Province(Grant Nos.202001BC070001,202102AA100053,202105AD160008,202207AA110003)the Innovation Team of Chronic Kidney Disease with Integrated Traditional Chinese and Western Medicine(No.2019KCXTD014).
文摘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.
