Program in Molecular Medicine; Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Immunotherapy | Infectious Disease | Microbiology | Molecular Biology | Virus Diseases
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.
PTC299, SARS-CoV-2, COVID-19, antiviral, cytokine, DHODH, coronavirus, cytokine storm
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 2020.08.05.238394; doi: https://doi.org/10.1101/2020.08.05.238394. Link to preprint on bioRxiv service.
Now published in Virus Research, doi: 10.1016/j.virusres.2020.198246
Luban J, Strambio De Castilla C, Wang Y, Jacobson A, Peltz S. (2020). The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.08.05.238394. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1733
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