Heterogeneous nuclear ribonucleoprotein A2B1, a novel drug target for hepatitis B virus infection

Abstract

10 HBV infection is a major global health burden that needs novel 11 immunotherapeutic approaches. Herein, we show that heterogeneous nuclear 12 ribonucleoprotein A2B1 (hnRNPA2B1) is a novel drug target for HBV infection. 13 We reveal the new target with highly selective probes of PAC5, a natural 14 sesquiterpene derivative. PAC5 show potent anti-HBV activity in vivo and in 15 vitro. Further studies on its mode of action indicate that PAC5 binds to the 16 residue Asp49 and a deep groove in the RNA recognition motif1 (RRM1) region 17 of hnRNPA2B1. PAC5-bound hnRNPA2B1 is activated, dimerized, and 18 translocated to the cytoplasm where it activates the TBK1-IRF3 pathway, 19 leading to the production of type I interferons (IFNs). Furthermore, PAC5 also 20 suppresses other viral replications, such as SARS-CoV-2 and vesicular 21 stomatitis virus (VSV). Our results indicate that PAC5 is the first small molecule 22 agonist of hnRNPA2B1, a drug target potentially valid for broad-spectrum viral 23 infections, providing a novel strategy for viral immunotherapy. 24