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Antiviral Res . Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2

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  • Antiviral Res . Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2


    Antiviral Res


    . 2023 Apr 17;105606.
    doi: 10.1016/j.antiviral.2023.105606. Online ahead of print.
    Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2


    Yihua Li 1 , Kun Wang 2 , Hongmin Sun 1 , Shuo Wu 2 , Huiqiang Wang 2 , Yuanyuan Shi 1 , Xingxing Li 1 , Haiyan Yan 2 , Ge Yang 2 , Mengyuan Wu 2 , Yihong Li 1 , Xiaotian Ding 1 , Shuyi Si 3 , Jiandong Jiang 2 , Yu Du 4 , Yuhuan Li 5 , Bin Hong 6



    Affiliations

    Abstract

    The emergence of SARS-CoV-2 variants represents a major threat to public health and requires identification of novel therapeutic agents to address the unmet medical needs. Small molecules impeding viral entry through inhibition of spike protein priming proteases could have potent antiviral effects against SARS-CoV-2 infection. Omicsynin B4, a pseudo-tetrapeptides identified from Streptomyces sp. 1647, has potent antiviral activity against influenza A viruses in our previous study. Here, we found omicsynin B4 exhibited broad-spectrum anti-coronavirus activity against HCoV-229E, HCoV-OC43 and SARS-CoV-2 prototype and its variants in multiple cell lines. Further investigations revealed omicsynin B4 blocked the viral entry and might be related to the inhibition of host proteases. SARS-CoV-2 spike protein mediated pseudovirus assay supported the inhibitory activity on viral entry of omicsynin B4 with a more potent inhibition of Omicron variant, especially when overexpression of human TMPRSS2. Moreover, omicsynin B4 exhibited superior inhibitory activity in the sub-nanomolar range against CTSL, and a sub-micromolar inhibition against TMPRSS2 in biochemical assays. The molecular docking analysis confirmed that omicsynin B4 fits well in the substrate binding sites and forms a covalent bond to Cys25 and Ser441 in CTSL and TMPRSS2, respectively. In conclusion, we found that omicsynin B4 may serve as a natural protease inhibitor for CTSL and TMPRSS2, blocking various coronavirus S protein-driven entry into cells. These results further highlight the potential of omicsynin B4 as an attractive candidate as a broad-spectrum anti-coronavirus agent that could rapidly respond to emerging variants of SARS-CoV-2.

    Keywords: Antiviral; COVID-19; Cathepsin L; Omicsynin B4/antipain; Protease inhibitor; TMPRSS2.

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