Everything Old Is New Again: Inhibitors targeting a host factor DHODH involved in de novo pyrimidine biosynthesis, like Leflunomide/Teriflunomide, that are known to treat autoimmune disease, exhibited antiviral activity at low efficacy. By developing novel and highly potent DHODH inhibitors with favorable drug-likeness and pharmacokinetic profiles, the old drug target DHODH is refreshed to be an attractive host target for developing broad-spectrum antivirals against many severe infectious viruses including newly-emerged coronavirus SARS-CoV-2 through a dual action of both antiviral and immuno-regulation.