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.

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…28 Others found IAV replication was dependent on lipid metabolism. 160 However, in our hands, inhibitors of lipid metabolism were effective only in vitro. 28 We also identified BEZ235, a dual PI3K/mTOR inhibitor.…”

EZH2-mediated H3K27me3 inhibits ACE2 expression

“…ACE2 expression was reported to be upregulated after infection of various viruses [19]. Here, we examined the transcriptome of cells originated from human lung and found that 24-h infection of SARS-CoV-2, but not MERS-CoV [20] which does not use ACE2 as cell receptor, led to enhanced ACE2 expression ( Fig. 1b), probably accelerating replication and spread of the coronavirus.…”

Metabolic host response and therapeutic approaches to influenza infection

“…In this regard, the results of a study revealed that influenza infection could induce fatty acid biosynthesis and cholesterol metabolism in human lung basal epithelial tumor cells [87]. Since SREBPs are thoroughly identified as stimulators of expression of many genes involved in lipid and sterol biosynthesis, including fatty acid synthase [102][103][104], their upregulation by the influenza virus (through induction of mTORC1 signaling, as discussed earlier) may logically explain the increased rate of lipogenesis [105]. A coincidence between increased fatty acid synthesis and a decline in fatty acid β-oxidation has been found during influenza infection, which is attributed to a variety of mechanisms directly or indirectly related to viral replication.…”

“…Studies have shown that these factors can play a variety of roles, such as energy supply and post-translational protein modification, as well as in the propagation of various groups of viruses such as influenza viruses. A study has shown that the AM580 compound, which is a retinoid derivative, inhibits SREBP-linked pathways, and it has antiviral activity against influenza A and coronavirus in vitro and in vivo [105].…”