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

Abstract

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