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Published on: January 22, 2019
The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines
Jeremy Luban1, Rachel A Sattler2, Elke Mühlberger3
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605, USA; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA, 02142, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA.
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.
Insights
PTC299, an orally bioavailable drug, effectively inhibits SARS-CoV-2 replication by targeting the DHODH enzyme. This compound also reduces inflammatory cytokines, showing promise as a COVID-19 therapeutic.
Area of Science:
- Virology and Immunology
- Drug Discovery and Development
Background:
- The COVID-19 pandemic necessitates novel therapeutics targeting SARS-CoV-2 and associated inflammation.
- Dihydroorotate dehydrogenase (DHODH) is a key enzyme in pyrimidine biosynthesis, crucial for viral replication and immune responses.
Purpose of the Study:
- To evaluate the anti-COVID-19 potential of PTC299, an orally bioavailable DHODH inhibitor.
- To assess PTC299's efficacy in inhibiting SARS-CoV-2 replication and modulating inflammatory cytokine production.
Main Methods:
- In vitro assessment of PTC299's antiviral activity against SARS-CoV-2 using tissue culture models.
- Determination of dose-dependent inhibition and selectivity index.
- Evaluation of PTC299's effect on cytokine production (IL-6, IL-17A, IL-17 F, VEGF) in relevant models.
Main Results:
- PTC299 demonstrated potent, dose-dependent, and DHODH-dependent inhibition of SARS-CoV-2 replication (EC50 range, 2.0-31.6 nM) with a high selectivity index (>3,800).
- PTC299 also inhibited replication of other RNA viruses, including Ebola virus.
- The compound significantly reduced the production of key inflammatory cytokines, including IL-6, IL-17A, IL-17 F, and VEGF.
Conclusions:
- PTC299 exhibits strong anti-SARS-CoV-2 activity through DHODH inhibition.
- Its ability to suppress key inflammatory mediators suggests a dual therapeutic mechanism for COVID-19.
- Combined with favorable pharmacokinetics and safety profiles, PTC299 is a promising candidate for COVID-19 treatment.
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