Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.238394v1?rss=1 Authors: Luban, J., Sattler, R., Muhlberger, E., Graci, J. D., Cao, L., Weetall, M., Trotta, C., Colacino, J. M., Bavari, S., Strambio-De-Castillia, C., Suder, E. L., Wang, Y., Soloveva, V., Cintron-Lue, K., Naryshkin, N. A., Pykett, M., Welch, E. M., O'Keefe, K., Kong, R., Goodwin, E., Jacobson, A., Paessler, S., Peltz, S. 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 (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. Copy rights belong to original authors. Visit the link for more info