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The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

Luban et al., Virus Research, doi:10.1016/j.virusres.2020.198246
Jan 2021  
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In Vitro study showing that PTC299, a dihydroorotate dehydrogenase inhibitor, inhibited SARS-CoV-2 replication with an EC50 of 1.96-31.6 nM and reduced inflammatory cytokine production. PTC299 had broad antiviral activity against HCV, poliovirus, ebola, and Rift Valley Fever viruses. The antiviral effect was reversed by addition of uridine, consistent with inhibition of pyrimidine synthesis. PTC299 reduced IL-6, IL-17, and VEGF production which may help prevent cytokine storm in COVID-19.
Luban et al., 31 Jan 2021, peer-reviewed, 23 authors. Contact: speltz@ptcbio.com.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperEmvododstatAll
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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