A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron<i>in vivo</i>
Daming Zuo, Yu Chen, Jian‐Piao Cai, Hao-Yang Yuan, Junqi Wu, Yue Yin, Jingwen Xie, Jingmin Lin, Jia Luo, Yang Feng, Longjiao Ge, Jia Zhou, Ronald J. Quinn, Sanjun Zhao, Xing Tong, Dong‐Yan Jin, Shuofeng Yuan, Shao‐Xing Dai, Min Xu
Abstract
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.