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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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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

    Biorxiv : the Preprint Server for Biology
    |August 15, 2020
    PubMed

    Insights

    PTC299, an oral drug, effectively inhibits SARS-CoV-2 replication and reduces inflammatory cytokines. This dihydroorotate dehydrogenase inhibitor shows promise as a COVID-19 therapeutic.

    Area of Science:

    • Virology
    • Immunology
    • Pharmacology

    Background:

    • The COVID-19 pandemic necessitates novel therapeutics targeting SARS-CoV-2 and associated inflammation.
    • Advanced COVID-19 illness is characterized by severe, fulminant inflammation.

    Approach:

    • PTC299, an orally available dihydroorotate dehydrogenase (DHODH) inhibitor, was investigated for anti-COVID-19 activity.
    • Inhibition of the de novo pyrimidine biosynthesis pathway by PTC299 was assessed.
    • The compound's effects on SARS-CoV-2 replication and cytokine production were evaluated in vitro.

    Key Points:

    • PTC299 demonstrated potent, dose-dependent, and DHODH-dependent inhibition of SARS-CoV-2 replication (EC50 range, 2.0–31.6 nM) with high selectivity (>3,800).
    • The compound also inhibited replication of other RNA viruses, including Ebola virus.
    • PTC299 suppressed the production of key inflammatory cytokines such as IL-6, IL-17A, IL-17F, and VEGF in vitro.

    Conclusions:

    • PTC299 exhibits dual activity: direct antiviral effects against SARS-CoV-2 and suppression of inflammatory cytokine production.
    • Its favorable pharmacokinetic and safety profiles, combined with demonstrated efficacy, position PTC299 as a promising therapeutic candidate for COVID-19.

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