The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

Luban, Jeremy; Sattler, Rachel; Mühlberger, Elke; Graci, Jason D.; Cao, Liangxian; Weetall, Marla; Trotta, Christopher; Colacino, Joseph M.; Bavari, Sina; Strambio-De-Castillia, Caterina; Suder, Ellen L.; Wang, Yetao; Soloveva, Veronica; Cintron-Lue, Katherine; Naryshkin, Nikolai A.; Pykett, Mark; Welch, Ellen M.; O’Keefe, Kylie; Kong, Ronald; Goodwin, Elizabeth; Jacobson, Allan; Paessler, Slobodan; Peltz, Stuart

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.