Related Experiment Video
Updated: May 8, 2025
Assays for the Identification of Novel Antivirals against Bluetongue Virus
Published on: October 11, 2013
Targeting host integrated stress response: lead discovery of flavonoid compounds active against coronaviruses PEDV
Liang Yi1,2, Yishuai Wang2, Jiehuang Wang3
1Department of Medicinal Chemistry, School of Pharmacy, Shanghai Jiao Tong University Shanghai 200240 China.
Abstract:
Viral infections trigger the integrated stress response (ISR) in eukaryotic cells that leads to the activation of eIF2α kinases, the elevation of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and thereby the shutdown of global protein synthesis that viruses rely on to replicate. Coronaviruses and other viruses have evolved various subversion mechanisms to counteract the antiviral ISR. These intricate host-virus interactions may be exploited by pharmacologically activating the host ISR for the development of host-directed antivirals (HDAs), an increasingly relevant area of research. In this study, we have discovered a new class of flavonoid-based ISR activators that exhibit potent antiviral activity against porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV). PEDV and PDCoV are animal coronaviruses of great veterinary and economic importance, for which there are currently no effective therapeutics. The mechanistic study indicated that lead compounds 1-B and 1-C inhibit PEDV and PDCoV replication via upregulating eIF2α phosphorylation and thereby downregulating global protein synthesis in host cells, suggesting they are HDA antivirals.
Insights
Researchers discovered new flavonoid compounds that activate the host
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Viral infections activate the integrated stress response (ISR) in cells, leading to eIF2α kinase activation and phosphorylation, which halts protein synthesis essential for viral replication.
- Viruses have evolved mechanisms to counteract the antiviral ISR, presenting an opportunity for developing host-directed antivirals (HDAs).
- Porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV) are significant animal coronaviruses lacking effective treatments.
Purpose of the Study:
- To identify and characterize novel flavonoid-based activators of the ISR with antiviral properties.
- To evaluate the efficacy of these compounds against PEDV and PDCoV.
- To elucidate the mechanism of action for potential HDA development.
Main Methods:
- Screening of flavonoid compounds for ISR activation.
- Antiviral assays against PEDV and PDCoV.
- Mechanistic studies involving eIF2α phosphorylation and global protein synthesis analysis.
Main Results:
- Discovery of a new class of flavonoid-based ISR activators.
- Demonstrated potent antiviral activity of lead compounds 1-B and 1-C against PEDV and PDCoV.
- Compounds 1-B and 1-C were shown to upregulate eIF2α phosphorylation, downregulating global protein synthesis.
Conclusions:
- Flavonoid-based compounds can effectively activate the host ISR.
- Lead compounds 1-B and 1-C show promise as host-directed antivirals against PEDV and PDCoV.
- This study highlights a potential therapeutic strategy for coronaviral infections.
