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The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines #MMPMID33249060
Luban J; Sattler RA; Muhlberger E; Graci JD; Cao L; Weetall M; Trotta C; Colacino JM; Bavari S; Strambio-De-Castillia C; Suder EL; Wang Y; Soloveva V; Cintron-Lue K; Naryshkin NA; Pykett M; Welch EM; O'Keefe K; Kong R; Goodwin E; Jacobson A; Paessler S; Peltz SW
Virus Res 2021[Jan]; 292 (?): 198246 PMID33249060show ga
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 (EC(50) 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.
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Virus+Res 2021 ; 292 (?): 198246
