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

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 a...

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Autores principales: Li, Yihua, Wang, Kun, Sun, Hongmin, Wu, Shuo, Wang, Huiqiang, Shi, Yuanyuan, Li, Xingxing, Yan, Haiyan, Yang, Ge, Wu, Mengyuan, Li, Yihong, Ding, Xiaotian, Si, Shuyi, Jiang, Jiandong, Du, Yu, Li, Yuhuan, Hong, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier B.V. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110284/
https://www.ncbi.nlm.nih.gov/pubmed/37076089
http://dx.doi.org/10.1016/j.antiviral.2023.105606
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author Li, Yihua
Wang, Kun
Sun, Hongmin
Wu, Shuo
Wang, Huiqiang
Shi, Yuanyuan
Li, Xingxing
Yan, Haiyan
Yang, Ge
Wu, Mengyuan
Li, Yihong
Ding, Xiaotian
Si, Shuyi
Jiang, Jiandong
Du, Yu
Li, Yuhuan
Hong, Bin
author_facet Li, Yihua
Wang, Kun
Sun, Hongmin
Wu, Shuo
Wang, Huiqiang
Shi, Yuanyuan
Li, Xingxing
Yan, Haiyan
Yang, Ge
Wu, Mengyuan
Li, Yihong
Ding, Xiaotian
Si, Shuyi
Jiang, Jiandong
Du, Yu
Li, Yuhuan
Hong, Bin
author_sort Li, Yihua
collection PubMed
description 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 for broad-spectrum antiviral therapy that could rapidly respond to emerging variants of SARS-CoV-2.
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spelling pubmed-101102842023-04-18 Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2 Li, Yihua Wang, Kun Sun, Hongmin Wu, Shuo Wang, Huiqiang Shi, Yuanyuan Li, Xingxing Yan, Haiyan Yang, Ge Wu, Mengyuan Li, Yihong Ding, Xiaotian Si, Shuyi Jiang, Jiandong Du, Yu Li, Yuhuan Hong, Bin Antiviral Res Article 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 for broad-spectrum antiviral therapy that could rapidly respond to emerging variants of SARS-CoV-2. Elsevier B.V. 2023-06 2023-04-17 /pmc/articles/PMC10110284/ /pubmed/37076089 http://dx.doi.org/10.1016/j.antiviral.2023.105606 Text en © 2023 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Li, Yihua
Wang, Kun
Sun, Hongmin
Wu, Shuo
Wang, Huiqiang
Shi, Yuanyuan
Li, Xingxing
Yan, Haiyan
Yang, Ge
Wu, Mengyuan
Li, Yihong
Ding, Xiaotian
Si, Shuyi
Jiang, Jiandong
Du, Yu
Li, Yuhuan
Hong, Bin
Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title_full Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title_fullStr Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title_full_unstemmed Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title_short Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2
title_sort omicsynin b4 potently blocks coronavirus infection by inhibiting host proteases cathepsin l and tmprss2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110284/
https://www.ncbi.nlm.nih.gov/pubmed/37076089
http://dx.doi.org/10.1016/j.antiviral.2023.105606
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