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

doi:10.1016/j.virusres.2020.198246

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 GoodwinAllan Jacobson, Slobodan Paessler, Stuart W. Peltz

Pathology

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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 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 (EC₅₀ 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.

Original language	English (US)
Article number	198246
Journal	Virus Research
Volume	292
DOIs	https://doi.org/10.1016/j.virusres.2020.198246
State	Published - Jan 15 2021

Keywords

Antiviral
COVID-19
Coronavirus
Cytokine
Cytokine storm
DHODH
PTC299
SARS-CoV-2

ASJC Scopus subject areas

Virology
Infectious Diseases
Cancer Research

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10.1016/j.virusres.2020.198246

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Luban, J., Sattler, R. A., Mühlberger, 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., ... Peltz, S. W. (2021). The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines. Virus Research, 292, Article 198246. https://doi.org/10.1016/j.virusres.2020.198246

Luban, J, Sattler, RA, Mühlberger, E, Graci, JD, Cao, L, Weetall, M, Trotta, C, Colacino, JM, Bavari, S, Strambio-De-Castillia, C, Suder, EL, Wang, Y, Soloveva, V, Cintron-Lue, K, Naryshkin, NA, Pykett, M, Welch, EM, O'Keefe, K, Kong, R, Goodwin, E, Jacobson, A, Paessler, S & Peltz, SW 2021, 'The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines', Virus Research, vol. 292, 198246. https://doi.org/10.1016/j.virusres.2020.198246

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

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 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 (EC50 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.",

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doi = "10.1016/j.virusres.2020.198246",

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AU - Luban, Jeremy

AU - Sattler, Rachel A.

AU - Mühlberger, Elke

AU - Graci, Jason D.

AU - Cao, Liangxian

AU - Weetall, Marla

AU - Trotta, Christopher

AU - Colacino, Joseph M.

AU - Bavari, Sina

AU - Strambio-De-Castillia, Caterina

AU - Suder, Ellen L.

AU - Wang, Yetao

AU - Soloveva, Veronica

AU - Cintron-Lue, Katherine

AU - Naryshkin, Nikolai A.

AU - Pykett, Mark

AU - Welch, Ellen M.

AU - O'Keefe, Kylie

AU - Kong, Ronald

AU - Goodwin, Elizabeth

AU - Jacobson, Allan

AU - Paessler, Slobodan

AU - Peltz, Stuart W.

PY - 2021/1/15

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N2 - 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 (EC50 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.

AB - 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 (EC50 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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