tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Rachel Sattler[SUP] 2 [/SUP], Elke M?hlberger[SUP] 3 [/SUP], Jason D Graci[SUP] 4 [/SUP], Liangxian Cao[SUP] 4 [/SUP], Marla Weetall[SUP] 4 [/SUP], Christopher Trotta[SUP] 4 [/SUP], Joseph M Colacino[SUP] 4 [/SUP], Sina Bavari[SUP] 5 [/SUP], Caterina Strambio-De-Castillia[SUP] 6 [/SUP], Ellen L Suder[SUP] 7 [/SUP], Yetao Wang[SUP] 6 [/SUP], Veronica Soloveva[SUP] 5 [/SUP], Katherine Cintron-Lue[SUP] 4 [/SUP], Nikolai A Naryshkin[SUP] 4 [/SUP], Mark Pykett[SUP] 4 [/SUP], Ellen M Welch[SUP] 4 [/SUP], Kylie O'Keefe[SUP] 4 [/SUP], Ronald Kong[SUP] 4 [/SUP], Elizabeth Goodwin[SUP] 4 [/SUP], Allan Jacobson[SUP] 8 [/SUP], Slobodan Paessler[SUP] 2 [/SUP], Stuart Peltz[SUP] 9 [/SUP]
Affiliations
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 (EC[SUB]50[/SUB] 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
. 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[SUP] 1 [/SUP], Rachel Sattler[SUP] 2 [/SUP], Elke M?hlberger[SUP] 3 [/SUP], Jason D Graci[SUP] 4 [/SUP], Liangxian Cao[SUP] 4 [/SUP], Marla Weetall[SUP] 4 [/SUP], Christopher Trotta[SUP] 4 [/SUP], Joseph M Colacino[SUP] 4 [/SUP], Sina Bavari[SUP] 5 [/SUP], Caterina Strambio-De-Castillia[SUP] 6 [/SUP], Ellen L Suder[SUP] 7 [/SUP], Yetao Wang[SUP] 6 [/SUP], Veronica Soloveva[SUP] 5 [/SUP], Katherine Cintron-Lue[SUP] 4 [/SUP], Nikolai A Naryshkin[SUP] 4 [/SUP], Mark Pykett[SUP] 4 [/SUP], Ellen M Welch[SUP] 4 [/SUP], Kylie O'Keefe[SUP] 4 [/SUP], Ronald Kong[SUP] 4 [/SUP], Elizabeth Goodwin[SUP] 4 [/SUP], Allan Jacobson[SUP] 8 [/SUP], Slobodan Paessler[SUP] 2 [/SUP], Stuart Peltz[SUP] 9 [/SUP]
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 (EC[SUB]50[/SUB] 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