Paper

The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

Cao, Liangxian, Goodwin, Elizabeth, Pykett, Mark, Colacino, Joseph M, Soloveva, Veronica, Naryshkin, Nikolai A, Weetall, Marla, Welch, Ellen M, O'keefe, Kylie, Strambio-De-Castillia, Caterina, Bavari, Sina, Graci, Jason D, Wang, Yetao, Luban, Jeremy, Muhlberger, Elke, Trotta, Christopher, Cintron-Lue, Katherine, Jacobson, Allan, Suder, Ellen L, Sattler, Rachel, Kong, Ronald, Paessler, Slobodan, Peltz, Stuart

2020

Overview

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 (EC50 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. Competing Interest Statement J.L, E.M., S.B, C. S-D.-C., E.L.S., Y.W, and V.S. have no conflict of interest to declare. S.P. and R.S. received support from PTC Therapeutics for this work. J.D.G, L.C, M.W, C.T-L., N.A.N, J.M.C, M.P. E.M.W., K. O K., R.K, E.G., A.J. and S.P. are or were employed by PTC Therapeutic and have received salary compensation for time, effort, and hold or held financial interest in the company.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Coronaviruses / COVID-19 / Cytokines / Dihydroorotate dehydrogenase / Immunology / Immunomodulation / Interleukin 17 / Pandemics / Pharmacokinetics / Replication / RNA viruses / Severe acute respiratory syndrome coronavirus 2 / Tissue culture / Vascular endothelial growth factor / Wages & salaries