A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo

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.

Automated summary

The twenty-first century has witnessed more than ten major epidemics or pandemics, including the devastating COVID-19. There is an urgent need for novel antiviral drugs with broad-spectrum coverage. This study reports a new broad-spectrum antiviral compound called PAC5. Oral administration of PAC5 was found to eliminate HBV cccDNA and reduce antigen load in mouse models of HBV infection. Additionally, PAC5 significantly decreased viral loads and attenuated lung inflammation in a hamster model of SARS-CoV-2 omicron (BA.1) infection. The mechanism behind these effects involves activation of hnRNPA2B1 and the TBK1-IRF3 pathway, leading to the production of antiviral type I IFNs. These findings suggest that PAC5 could be a promising option for dealing with emerging infectious diseases.