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; Jun-qi WU; Yue Yin; Jing-wen Xie; Jing-min Lin; Jia Luo; Yang Feng; Long-jiao GE; Jia Zhou; Ronald J Quinn; San-jun Zhao; Xing Tong; Dong-yan Jin; Shuofeng Yuan; Shao-xing Dai; Min XU

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

Author: Daming ZUO ¹ ; Yu CHEN ¹ ; Jian-Piao CAI ² ; Hao-Yang YUAN ³ ; Jun-Qi WU ³ ; Yue YIN ¹ ; Jing-Wen XIE ¹ ; Jing-Min LIN ¹ ; Jia LUO ³ ; Yang FENG ³ ; Long-Jiao GE ^{4
,

5} ; Jia ZHOU ⁶ ; Ronald J QUINN ⁷ ; San-Jun ZHAO ⁸ ; Xing TONG ^{4
,

5} ; Dong-Yan JIN ⁹ ; Shuofeng YUAN ² ; Shao-Xing DAI ^{4
,

5} ; Min XU ³
Author Information

1. Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
2. Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China.
3. Center for Pharmaceutical Sciences, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
4. State Key Laboratory of Primate Biomedical Research
5. Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China.
6. Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
7. Griffith Institute for Drug Discovery, Griffith University, Brisbane 4111, Australia.
8. School of Life Sciences, Yunnan Normal University, Kunming 650500, China.
9. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: HBV; PAC5; SARS-CoV-2 omicron; TBK1-IRF3 pathway; hnRNPA2B1; type I IFNs
MeSH: Animals; Mice; Antiviral Agents/pharmacology*; COVID-19; Hepatitis B virus; Interferon Type I/metabolism*; SARS-CoV-2/drug effects*; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/antagonists & inhibitors*
From: Protein & Cell 2023;14(1):37-50
CountryChina
Language:English
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.