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

Luban, J.; Sattler, R.; Muhlberger, E.; Graci, J. D.; Cao, L.; Weetall, M.; Trotta, C.; Colacino, J. M.; Bavari, S.; Strambio-De-Castillia, C.; Suder, E. L.; Wang, Y.; Soloveva, V.; Cintron-Lue, K.; Naryshkin, N. A.; Pykett, M.; Welch, E. M.; O'Keefe, K.; Kong, R.; Goodwin, E.; Jacobson, A.; Paessler, S.; Peltz, S.

doi:10.1101/2020.08.05.238394

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bioRxiv · 10.1101/2020.08.05.238394

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

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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-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.

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Luban, J., Sattler, R., Muhlberger, E., Graci, J. D., Cao, L., Weetall, M., Trotta, C., Colacino, J. M., Bavari, S., Strambio-De-Castillia, C., Suder, E. L., Wang, Y., Soloveva, V., Cintron-Lue, K., Naryshkin, N. A., Pykett, M., Welch, E. M., O'Keefe, K., Kong, R., Goodwin, E., Jacobson, A., Paessler, S., Peltz, S.. 2020-08-05. The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines. https://doi.org/10.1101/2020.08.05.238394

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