Volume 14 Issue 1
Jan.  2023
Turn off MathJax
Article Contents
Daming Zuo, Yu Chen, Jian-piaoCai, 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. A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo[J]. Protein&Cell, 2023, 14(1): 37-50. doi: 10.1093/procel/pwac027
Citation: Daming Zuo, Yu Chen, Jian-piaoCai, 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. A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo[J]. Protein&Cell, 2023, 14(1): 37-50. doi: 10.1093/procel/pwac027

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

doi: 10.1093/procel/pwac027
  • Received Date: 2022-05-25
  • Rev Recd Date: 2022-06-09
  • Publish Date: 2023-01-01
  • 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.
  • loading
  • [1]
    Abedi MR, Dixon S, Guyon T, et al. Predicting COVID-19 vaccine efficacy from neutralizing antibody levels. medRxiv 2021:1–12.
    Alarcon CR, Goodarzi H, Lee H, et al. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 2015;162:1299–1308.
    Amin OE, Colbeck EJ, Daffis S, et al. Therapeutic potential of TLR8 agonist GS-9688 (Selgantolimod) in chronic hepatitis B: remodeling of antiviral and regulatory mediators. Hepatology (Hoboken, NJ, U S) 2021;74:55–71.
    Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19-final report. N Engl J Med 2020;383:1813–1826.
    Chen SF, Zhou YQ, Chen YR, et al. fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 2018;34:884–890.
    Chiba S, Kiso M, Nakajima N, et al. Co-administration of favipiravir and the remdesivir metabolite GS-441524 effectively reduces SARS-CoV-2 replication in the lungs of the syrian hamster model. mBio, 2022;e0304421.
    Daffis S, Balsitis S, Chamberlain J, et al. Toll-like receptor 8 agonist GS-9688 induces sustained efficacy in the woodchuck model of chronic hepatitis B. Hepatology (Hoboken, NJ, U S) 2021;73:53–67.
    Fanning Gregory C, Zoulim F, Hou J, et al. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov 2019;18:827–844.
    Gardner BJ, Kilpatrick AM. Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations. medRxiv 2021:1–24.
    Gonzalez-Navajas JM, Lee J, David M, et al. Immunomodulatory functions of type I interferons. Nat Rev Immunol 2012;12:125–135.
    Gordon H, Ajamian L, Valiente-Echeverria F, et al. Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA. RNA Biol 2013;10:1714–1725.
    Guo Q, Zhao Y, Li J, et al. Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19. Cell Host Microbe 2021;29:222–235.
    Kim D, Paggi JM, Park C, et al. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 2019;37:907–915.
    Le Guilloux V, Schmidtke P, Tuffery P. Fpocket: an open source platform for ligand pocket detection. BMC Bioinform 2009;10:168.
    Ledford H. Can drugs reduce the risk of long COVID? What scientists know so far. Nature (London, U K) 2022;604:20–21.
    Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment. Nat Rev Immunol 2020;20:585–586.
    Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features.Bioinformatics 2014;30:923–930.
    Liu Y, Shi SL. The roles of hnRNP A2/B1 in RNA biology and disease.Wiley Interdiscip Rev RNA 2021;12:e1612.
    McNab F, Mayer-Barber K, Sher A, et al. Type I interferons in infectious disease. Nat Rev Immunol 2015;15:87–103.
    Mueller U, Steinhoff U, Reis LFL, et al. Functional role of type I and type II interferons in antiviral defense. Science (Washington, DC) 1994;264:1918–1921.
    Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020;83:770–803.
    Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M-pro inhibitor clinical candidate for the treatment of COVID-19. Science 2021;374:1586–1593.
    Planas D, Saunders N, Maes P,et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature 2022;602:671–675.
    Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43:e47.
    Sadler AJ, Williams BRG. Interferon-inducible antiviral effectors. Nat Rev Immunol 2008;8:559–568.
    Schmidt A, Peters S, Knaus A, et al. TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19. NPJ Genom Med 2021;6:55.
    Sleigh A. Twenty-first century plague: the story of SARS. Nature 2005;435:886–887.
    Taft J, Markson M, Legarda D, et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 2021;184:4447–4463 e4420.
    Tao KM, Tzou PL, Nouhin J, et al. The biological and clinical significance of emerging SARS-CoV-2 variants. Nat Rev Genet 2021;22:757–773.
    Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455–461.
    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 2013;4:2980.
    Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature 2021;591:451–457.
    Wang L, Wen M, Cao X. Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses. Science 2019;365:656-+.
    Wu Y, Ma L, Zhuang Z, et al. Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling. Signal Transduct Target Ther 2020;5:221.
    Wu B, Su S, Patil DP, et al. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun 2018;9:420.
    Xia H, Cao Z, Xie X, et al. Evasion of type I interferon by SARS-CoV-2. Cell Rep 2020b;33:108234.
    Xia C, Tang W, Geng P, et al. Baicalin down-regulating hepatitis B virus transcription depends on the liver-specific HNF4α-HNF1α axis. Toxicol Appl Pharmacol 2020a;403:115131.
    Yang D, Liu LC, Zhu DM, et al. A mouse model for HBV immunotolerance and immunotherapy. Cell Mol Immunol 2014;11:71–78.
    Ying C, Li Y, Leung CH, et al. Unique antiviral mechanism discovered in anti-hepatitis B virus research with a natural product analogue. Proc Natl Acad Sci USA 2007;104:8526–8531.
    Yu G, Wang LG, Han Y, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012;16:284–287.
    Yuan S, Yin X, Meng X, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature 2021;593:418–423.
    Zhang Q, Bastard P, Effort CHG, et al. Human genetic and immunological determinants of critical COVID-19 pneumonia. Nature(London, U K) 2022;603:587–598.
    Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–273.
    Zhou D, Chan JF, Zhou B, et al. Robust SARS-CoV-2 infection in nasal turbinates after treatment with systemic neutralizing antibodies. Cell Host Microbe 2021;29: 551–563 e555.
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (171) PDF downloads(32) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint