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

Jeremy Luban, Rachel 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 Peltz
doi: https://doi.org/10.1101/2020.08.05.238394
Jeremy Luban
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
2Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
3Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA
4Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA
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Rachel Sattler
5Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
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Elke Mühlberger
4Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA
6Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
7National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA
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Jason D. Graci
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Liangxian Cao
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Marla Weetall
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Christopher Trotta
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Joseph M. Colacino
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Sina Bavari
9United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702, USA
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Caterina Strambio-De-Castillia
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Ellen L. Suder
6Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
7National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA
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Yetao Wang
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Veronica Soloveva
9United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702, USA
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Katherine Cintron-Lue
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Nikolai A. Naryshkin
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Mark Pykett
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Ellen M. Welch
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Kylie O’Keefe
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Ronald Kong
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Elizabeth Goodwin
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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Allan Jacobson
10Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Slobodan Paessler
5Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
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Stuart Peltz
8PTC Therapeutics, Inc. South Plainfield, NJ 07080, USA
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  • For correspondence: speltz@ptcbio.com
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SUMMARY

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.

Competing Interest Statement

J.L, E.M., S.B, C. S-D.-C., E.L.S., Y.W, and V.S. have no conflict of interest to declare. S.P. and R.S. received support from PTC Therapeutics for this work. J.D.G, L.C, M.W, C.T-L., N.A.N, J.M.C, M.P. E.M.W., K. O K., R.K, E.G., A.J. and S.P. are or were employed by PTC Therapeutic and have received salary compensation for time, effort, and hold or held financial interest in the company.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
Jeremy Luban, Rachel 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 Peltz
bioRxiv 2020.08.05.238394; doi: https://doi.org/10.1101/2020.08.05.238394
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The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
Jeremy Luban, Rachel 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 Peltz
bioRxiv 2020.08.05.238394; doi: https://doi.org/10.1101/2020.08.05.238394

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