Phytochemical alkaloids orchestrate immunometabolism against viral infections

The role of cholesterol metabolism in antiviral immunity has been established, but if and how this cholesterol-mediated immunometabolism can be regulated by specific small molecules is of particular interest in the quest for novel antiviral therapeutics. Here, we first demonstrate that NPC1 is the key cholesterol transporter for suppressing viral replication by changing cholesterol metabolism and triggering the innate immune response via systemic analyses of all possible cholesterol transporters. We then use the Connectivity Map (CMap), a systematic methodology for identifying functional connections between genetic perturbations and drug actions, to screen NPC1 inhibitors, and found that bis-benzylisoquinoline alkaloids (BBAs) exhibit high efficacy in the inhibition of viral infections. Among all potent BBAs that we tested, tetrandrine (Tet) is the most effective, by directly binding to NPC1 and inducing lysosomal cholesterol accumulation in order to resist viral entries. Through the NPC1-STING interface mechanism, Tet further blocks STING lysosomal degradation which leads to boosting of the interferon-based antiviral response against multiple viruses both <i>in vitro</i> and <i>in vivo</i>. Therefore, BBAs represent very promising drug compounds for this newly discovered antiviral mechanism by targeting the NPC1-STING interface via cholesterol-mediated immunometabolism, which in turn disrupts the virus life cycle and boosts antiviral immunity.