Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
Microbiome Medicine Center, Department of Laboratory medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.
Protein Cell. 2022 Jul 15;14(1):37-50. doi: 10.1093/procel/pwac027. eCollection 2023 Jan.
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.
二十一世纪已经记录了十多次重大病毒性疾病的爆发或大流行，包括毁灭性的 COVID-19。目前迫切需要新型、有效、广谱的抗病毒药物。在此，我们报告了一种新型广谱抗病毒化合物 PAC5。PAC5 的口服给药可消除 HBV cccDNA，并减少乙型肝炎病毒感染的不同小鼠模型中的大抗原负荷。引人注目的是，PAC5 在 SARS-CoV-2 奥密克戎（BA.1）感染的仓鼠模型中的口服给药可显著降低病毒载量并减轻肺部炎症。从机制上讲，PAC5 结合到 hnRNPA2B1 的 RNA 识别基序中 Asp49 附近的一个口袋中。PAC5 结合的 hnRNPA2B1 被广泛激活并易位到细胞质中，在那里它启动 TBK1-IRF3 途径，导致产生具有抗病毒活性的 I 型干扰素。我们的研究结果表明，PAC5 是 hnRNPA2B1 的新型小分子激动剂，它可能在应对当前和未来的新发传染病方面发挥作用。
