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Virus Res
. 2020 Nov 26;198246.
doi: 10.1016/j.virusres.2020.198246. Online ahead of print.
The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
Jeremy Luban 1 , Rachel Sattler 2 , Elke M?hlberger 3 , Jason D Graci 4 , Liangxian Cao 4 , Marla Weetall 4 , Christopher Trotta 4 , Joseph M Colacino 4 , Sina Bavari 5 , Caterina Strambio-De-Castillia 6 , Ellen L Suder 7 , Yetao Wang 6 , Veronica Soloveva 5 , Katherine Cintron-Lue 4 , Nikolai A Naryshkin 4 , Mark Pykett 4 , Ellen M Welch 4 , Kylie O'Keefe 4 , Ronald Kong 4 , Elizabeth Goodwin 4 , Allan Jacobson 8 , Slobodan Paessler 2 , Stuart Peltz 9
Affiliations
- PMID: 33249060
- DOI: 10.1016/j.virusres.2020.198246
Abstract
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-17 F, 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.
Keywords: COVID-19; DHODH; PTC299; SARS-CoV-2; antiviral; coronavirus; cytokine; cytokine storm