University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Program in Molecular Medicine; Department of Microbiology and Physiological Systems
Publication Date
2020-08-05
Document Type
Article Preprint
Disciplines
Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Immunotherapy | Infectious Disease | Microbiology | Molecular Biology | Virus Diseases
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 (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.
Keywords
PTC299, SARS-CoV-2, COVID-19, antiviral, cytokine, DHODH, coronavirus, cytokine storm
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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
10.1101/2020.08.05.238394
Source
bioRxiv 2020.08.05.238394; doi: https://doi.org/10.1101/2020.08.05.238394. Link to preprint on bioRxiv service.
Journal/Book/Conference Title
bioRxiv
Repository Citation
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. 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
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Enzymes and Coenzymes Commons, Immunology of Infectious Disease Commons, Immunoprophylaxis and Therapy Commons, Immunotherapy Commons, Infectious Disease Commons, Microbiology Commons, Molecular Biology Commons, Virus Diseases Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.