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Dual mechanism of action of PTC299 and other DHODH inhibitors in suppressing SARS-CoV-2 replication and cellular cytokine storms

Stuart W. Peltz, Elizabeth Goodwin, Marla Weetall, Jason D. Graci, Ellen M. Welch, Kylie O'Keefe, Allan Jacobson, Allan Jacobson, Allan Jacobson

COVID-19, the pandemic arising from the third coronavirus outbreak in the past 20 years, will not be the last. Identifying therapies for COVID-19, and possibly future outbreaks, is of great importance. COVID-19 is characterized by an initial phase of viral replication followed by an excessive pro-inflammatory response (cytokine storm). PTC299 is an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo pyrimidine biosynthesis pathway. Recent in vitro findings indicate that PTC299 acts via a dual mechanism to inhibit viral replication and the cytokine storm, both of which are dependent on intracellular pyrimidine levels. Consistent with PTC299 targeting a host enzyme, the drug demonstrates broad antiviral activity, and is likely to be impervious to viral resistance. These characteristics may be critical when SARS-CoV-2 becomes endemic or mutates sufficiently to be resistant to current vaccines, as well as during future coronavirus outbreaks.