Identification of Sterol Regulatory Element Binding Protein-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. Integrative transcriptomic and lipidomic analysis with simultaneous mapping of dysregulated gene expression and dysregulated lipids showed that the glycerophospholipid metabolism was the most affected pathway in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). Screening of a bioactive lipid mediators library showed that AM580, a retinoid derivative and RAR-α agonist, is highly potent in interrupting the life cycle of a broad spectrum of viruses, including MERS-CoV, SARS-CoV, influenza viruses, Zika virus, enteroviruses, and adenovirus. Treatment with AM580 significantly improved the survival rate, body weight, and viral load of human dipeptidyl-peptidase 4-transgenic mice infected with MERSCoV. Using click chemistry, the overexpressed sterol regulatory element binding protein (SREBP) was shown to interact with AM580, which accounts for its broad-spectrum antiviral activity. Our study showed that AM580 exhibits broadspectrum antiviral activity against various emerging and respiratory viruses via disruption of the host lipid metabolism. Further studies should be conducted to elicit the full spectrum of viruses that can be inhibited by the broad-spectrum AM580 and the downstream lipid biosynthesis pathways involved in AM580-treated cells.