Dihydromyricetin is a new inhibitor of influenza polymerase PB2 subunit and influenza-induced inflammation.

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.

• Authors: Yuanxin Tian, Huiting Sang, Miaomiao Liu, Fangzhao Chen, Yingna Huang, Lin Li, Shuwen Liu, Jie Yang
• Journal: Microbes and infection (Microbes Infect) 2020 Jul - Aug Vol. 22 Issue 6-7 Pg. 254-262 ISSN: 1769-714X [Electronic] France
• PMID: 32554102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antiviral Agents
• Cytokines
• Flavonols
• PB2 protein, Influenzavirus A
• TLR3 protein, human
• Toll-Like Receptor 3
• Viral Proteins
• RNA-Dependent RNA Polymerase
• dihydromyricetin
• Zanamivir

Topics

• Animals
• Anti-Inflammatory Agents (metabolism, pharmacology)
• Antiviral Agents (metabolism, pharmacology)
• Binding Sites
• Cell Line
• Cytokines (metabolism)
• Drug Synergism
• Flavonols (metabolism, pharmacology)
• Humans
• Inflammation
• Influenza A virus (drug effects)
• Protein Binding
• RNA-Dependent RNA Polymerase (antagonists & inhibitors, chemistry, metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptor 3 (metabolism)
• Viral Proteins (antagonists & inhibitors, chemistry, metabolism)
• Virus Replication (drug effects)
• Zanamivir (pharmacology)