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

Abstract

Viruses are obligate intracellular microbes that exploit the host metabolic machineries to meet their biosynthetic demands, making these host pathways potential therapeutic targets. Here, by exploring a lipid library, we show that AM580, a retinoid derivative and RAR-α agonist, is highly potent in interrupting the life cycle of diverse viruses including Middle East respiratory syndrome coronavirus and influenza A virus. Using click chemistry, the overexpressed sterol regulatory element binding protein (SREBP) is shown to interact with AM580, which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Collectively, our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as a potential target for the development of broad-spectrum antiviral strategies.

Cited by papers we hold 8

• Metabolic Alterations in SARS-CoV-2 Infection and Its Implication in Kidney Dysfunction · 2021
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• Host and viral determinants for efficient SARS-CoV-2 infection of the human lung · 2021
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• Metabolic host response and therapeutic approaches to influenza infection · 2020
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• A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19 · 2020
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• Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators · 2020
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• The Role of Lipid Metabolism in COVID-19 Virus Infection and as a Drug Target · 2020
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• Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication · 2019
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• Hijacking the Supplies: Metabolism as a Novel Facet of Virus-Host Interaction · 2019
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