Dihydromyricetin is a new inhibitor of influenza polymerase PB2 subunit and influenza-induced inflammation |
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Institution: | 1. Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China;2. School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China;1. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China;2. Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China;1. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan;2. Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, Istanbul, Turkey;3. Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;4. Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan;1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China;2. State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, PR China |
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Abstract: | Development of new and effective anti-influenza drugs is critical for the treatment of influenza virus infection. The polymerase basic 2 (PB2) subunit as a core subunit of influenza A virus RNA polymerase complex is considered to be an attractive drug target for anti-influenza drug discovery. Dihydromyricetin, as a natural flavonoid, has a wide range of biological activities, but its anti-influenza A virus activity is ambiguous. Here, we found dihydromyricetin could inhibit the replication of a variety of influenza A virus strains. Mechanism studies demonstrated that dihydromyricetin reduced viral polymerase activity via selective inhibition of viral PB2 subunit, and decreased relative amounts of viral mRNA and genomic RNA during influenza A virus infection. The binding affinity and molecular docking analyses revealed that dihydromyricetin interacted with the PB2 cap-binding pocket, functioned as a cap-binding competitor. Interestingly, dihydromyricetin also reduced cellular immune injury by inhibiting TLR3 signaling pathway. Additionally, combination treatment of dihydromyricetin with zanamivir exerted a synergistic anti-influenza effect. Altogether, our experiments reveal the antiviral and anti-inflammatory activities of dihydromyricetin in vitro against influenza virus infection, which provides a new insight into the development of novel anti-influenza drugs. |
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Keywords: | Dihydromyricetin Influenza A virus Influenza polymerase basic 2 Anti-inflammatory TLR3 |
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