The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
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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 (EC 50 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.
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SciScore for 10.1101/2020.08.05.238394: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources , Vero (ATCC, CCL-81), Vero E6 cells (ATCC, CRL-1586) were maintained at 37°C and 5% CO2 in Dulbecco’s Modified Eagle Medium (DMEM, Hyclone or GIBCO) supplemented with 10% Fetal Bovine Serum (FBS, Corning or GIBCO). Verosuggested: ATCC Cat# CRL-1586, RRID:CVCL_0574)Vero E6suggested: NoneHuh7 cell line harboring a genotype 1b replicon was maintained under similar conditions but with the addition of 0.25 mg/ml G418 (GIBCO). Huh7suggested: …SciScore for 10.1101/2020.08.05.238394: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources , Vero (ATCC, CCL-81), Vero E6 cells (ATCC, CRL-1586) were maintained at 37°C and 5% CO2 in Dulbecco’s Modified Eagle Medium (DMEM, Hyclone or GIBCO) supplemented with 10% Fetal Bovine Serum (FBS, Corning or GIBCO). Verosuggested: ATCC Cat# CRL-1586, RRID:CVCL_0574)Vero E6suggested: NoneHuh7 cell line harboring a genotype 1b replicon was maintained under similar conditions but with the addition of 0.25 mg/ml G418 (GIBCO). Huh7suggested: NoneThe received virus was amplified in HeLa cells, grown in DMEM supplemented with 5% FBS and 1% penicillin and streptomycin solution and the titer evaluated by plaque assay on HeLa cell monolayers. HeLasuggested: CLS Cat# 300194/p772_HeLa, RRID:CVCL_0030)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04439071 Recruiting A Study to Evaluate Efficacy and Safety of PTC299 in Hospita… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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