@article{f483d628dd8c4cda97be117ee36c74b0,
title = "The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines",
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 bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS−COV-2 replication (EC50 range, 2.0–31.6 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-17 F, 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.",
keywords = "Antiviral, COVID-19, Coronavirus, Cytokine, Cytokine storm, DHODH, PTC299, SARS-CoV-2",
author = "Jeremy Luban and Sattler, {Rachel A.} and Elke M{\"u}hlberger and Graci, {Jason D.} and Liangxian Cao and Marla Weetall and Christopher Trotta and Colacino, {Joseph M.} and Sina Bavari and Caterina Strambio-De-Castillia and Suder, {Ellen L.} and Yetao Wang and Veronica Soloveva and Katherine Cintron-Lue and Naryshkin, {Nikolai A.} and Mark Pykett and Welch, {Ellen M.} and Kylie O'Keefe and Ronald Kong and Elizabeth Goodwin and Allan Jacobson and Slobodan Paessler and Peltz, {Stuart W.}",
note = "Funding Information: The study was supported by NIH grants R37AI147868 and R01AI148784 to J.L, a grant from the Evergrande COVID-19 Response Fund Award from the Massachusetts Consortium on Pathogen Readiness to J.L. E.M. was supported by the Evergrande COVID-19 Response Fund Award from the Massachusetts Consortium on Pathogen Readiness, Fast Grants, and NIH NCATS grant UL1TR001430. E.S. was supported by NIH HL007035T32 training grant Biology of the Lung. S.B. was supported by the Defense Threat Reduction Agency , Joint Science Technology Office , A.J was supported by the NIH grant R35GM122468, and S.P. and R.A.S were supported through Sponsored Research Agreement from PTC Therapeutics to University of Texas Medical Branch . R.A.S was also funded in part by the Clinical and Translational Science Award NRSA (TL1) Training Core grant TL1TR001440 from the National Center for Advancing Translational Sciences at the NIH. Publisher Copyright: {\textcopyright} 2020",
year = "2021",
month = jan,
day = "15",
doi = "10.1016/j.virusres.2020.198246",
language = "English (US)",
volume = "292",
journal = "Virus Research",
issn = "0168-1702",
publisher = "Elsevier",
}