SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Viruses rely on host cell metabolic pathways for replication, presenting them as potential therapeutic targets.
• Retinoids and their derivatives have shown promise in modulating cellular processes, but their broad antiviral potential is underexplored.

Purpose of the Study:

• To identify novel compounds that inhibit viral replication by targeting host metabolic pathways.
• To investigate the mechanism of action of AM580, a retinoid derivative, against diverse viruses.

Main Methods:

• Screening of a lipid library to identify antiviral compounds.
• Utilizing click chemistry to investigate molecular interactions.
• Performing mechanistic studies on viral replication pathways and host lipid biosynthesis.

Main Results:

• AM580 demonstrated potent broad-spectrum antiviral activity against Middle East respiratory syndrome coronavirus and influenza A virus.
• AM580 interacts with overexpressed sterol regulatory element binding protein (SREBP), explaining its wide-ranging efficacy.
• SREBP proteolytic processes and downstream lipid biosynthesis, including viral protein palmitoylation and double-membrane vesicle formation, are critical for viral replication and are targeted by AM580.

Conclusions:

• The study identifies a lipogenic transactivation event involving SREBP as a critical vulnerability in human viral infections.
• SREBP represents a promising therapeutic target for developing novel broad-spectrum antiviral strategies.
• AM580 serves as a lead compound for further development of antiviral agents targeting host lipid metabolism.