摘要
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.
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).
