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.
journal_name
Virus Resjournal_title
Virus researchauthors
Luban J,Sattler RA,Mühlberger 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,Jacdoi
10.1016/j.virusres.2020.198246subject
Has Abstractpub_date
2021-01-15 00:00:00pages
198246eissn
0168-1702issn
1872-7492pii
S0168-1702(20)31153-9journal_volume
292pub_type
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