Journal of Cytokine Biology
Open Access

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

Stuart W. Peltz^1*, Elizabeth Goodwin¹, Marla Weetall¹, Jason D. Graci¹, Ellen M. Welch¹, Kylie O\'Keefe¹, Allan Jacobson², Allan Jacobson¹ and Allan Jacobson²

¹PTC Therapeutics, Inc. South Plainfield, NJ, 07080, U.S.A

²Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, U.S.A

Citation: Peltz SW, Goodwin E, Weetall M, Graci JD, Welch EM,et al. (2021) Dual Mechanism of Action of PTC299 and other DHOHD Inhibitors in Suppressing SARS-CoV-2 Replication and Cellular Cytokine Storms. J Cytokine Biol 6:2:100037.

Copyright: © 2021 Peltz SW, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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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.