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

作者：Zuo, Daming^*; Chen, Yu; Cai, Jian-piao; Yuan, Hao-Yang; Wu, Jun-Qi; Yin, Yue; Xie, Jing-Wen; Lin, Jing-Min; Luo, Jia; Feng, Yang; Ge, Long-Jiao; Zhou, Jia; Quinn, Ronald J.; Zhao, San-Jun; Tong, Xing; Jin, Dong-Yan; Yuan, Shuofeng^*; Dai, Shao-Xing^*; Xu, Min^*

来源：Protein & Cell, 2023, 14(1): 37-50.

DOI：10.1093/procel/pwac027

• PAC5
• HBV
• SARS-CoV-2 omicron
• TBK1-IRF3 pathway
• type I IFNs

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.

• 单位
  南方医科大学