The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines
Jeremy Luban, Rachel A Sattler, Elke Mühlberger, Jason D Graci, Liangxian Cao, Marla Weetall, Christopher Trotta, Joseph M Colacino, Sina Bavari, Caterina Strambio-De-Castillia, Ellen L Suder, Yetao Wang, Veronica Soloveva, Katherine Cintron-Lue, Nikolai A Naryshkin, Mark Pykett, Ellen M Welch, Kylie O’keefe, Ronald Kong, Elizabeth Goodwin, Allan Jacobson, Slobodan Paessler, Stuart W Peltz
Virus Research, doi:10.1016/j.virusres.2020.198246
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 bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC 50 range, 2.0-31.6 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.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10. 1016/j.virusres.2020.198246.
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