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Myricetin exerts its antiviral activity against infectious bronchitis virus by inhibiting the deubiquitinating activity of papain-like protease.

ABSTRACT: Infectious bronchitis virus (IBV) is a causative agent that causes severe economic losses in the poultry industry worldwide. Papain-like protease (PLpro) is a nonstructural protein encoded by IBV. It has deubiquitinating enzyme activity, which can remove the ubiqutin modification from the protein in nuclear factor kappa-B (NF-κB) and interferon regulatory factor 7 (IRF7) signaling pathway, so as to negatively regulate the host's innate immune response to promote viral replication. In this study, PLpro was selected as the target to screen antiviral agents against IBV. Through protein prokaryotic expression technology, we successfully expressed the active IBV PLpro. Among the 16 natural products, myricetin showed the strongest inhibitory effect on IBV PLpro. Next, we tested the antiviral activity of myricetin against IBV and verified whether it can exert antiviral activity by inhibiting the deubiquitinating activity of PLpro. The results showed that myricetin can significantly inhibit IBV replication in primary chicken embryo kidney (CEK) cells and it can significantly upregulate the transcription levels in the NF-κB and IRF7 signaling pathways. Moreover, we verified that myricetin can increase the ubiquitin modification level on tumor necrosis factor receptor-associated factor 3 and 6 (TRAF3 and TRAF6) reduced by IBV PLpro. In conclusion, these results indicated that myricetin exerts antiviral activity against IBV by inhibiting the deubiquitinating activity of PLpro, which can provide new perspective for the prevention and treatment of IBV.

SUBMITTER: Peng S

PROVIDER: S-EPMC8741506 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hypericum perforatum L., also known as Saint John's Wort, has been well studied for its chemical composition and pharmacological activity. In this study, the antiviral activities of H. perforatum on infectious bronchitis virus (IBV) were evaluated in vitro and in vivo for the first time. The results of in vitro experiments confirmed that the antiviral component of H. perforatum was ethyl acetate extraction section (HPE), and results showed that treatment with HPE significantly reduced the relative messenger ribonucleic acid (mRNA) expression and virus titer of IBV, and reduced positive green immunofluorescence signal of IBV in chicken embryo kidney (CEK) cells. HPE treatment at doses of 480-120 mg/kg for 5 days, reduced IBV induced injury in the trachea and kidney, moreover, reduced the mRNA expression level of IBV in the trachea and kidney in vivo. The mRNA expression levels of IL-6, tumor necrosis factor alpha (TNF-?), and nuclear factor kappa beta (NF-?B) significantly decreased, but melanoma differentiation-associated protein 5 (MDA5), mitochondrial antiviral signaling gene, interferon alpha (IFN-?), and interferon beta (IFN-?) mRNA levels significantly increased in vitro and in vivo. Our findings demonstrated that HPE had significant anti-IBV effects in vitro and in vivo, respectively. In addition, it is possible owing to up-regulate mRNA expression of type I interferon through the MDA5 signaling pathway and down-regulate mRNA expression of IL-6 and TNF-? via the NF-?B signaling pathway. Moreover, the mainly active compositions of HPE analyzed by high-performance liquid chromatography/electrospray ionization-mass spectroscopy (ESI-MS) are hyperoside, quercitrin, quercetin, pseudohypericin, and hypericin, and a combination of these compounds could mediate the antiviral activities. This might accelerate our understanding of the antiviral effect of H. perforatum and provide new insights into the development of effective therapeutic strategies.

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Myricetin exerts its antiviral activity against infectious bronchitis virus by inhibiting the deubiquitinating activity of papain-like protease.

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