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.

中文翻译：

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DHODH抑制剂PTC299阻止SARS-CoV-2复制并抑制炎性细胞因子的诱导。

冠状病毒病2019（COVID-19）大流行迫切需要抑制SARS-CoV-2病毒并抑制晚期疾病爆发性炎症特征的疗法。在这里，我们描述了PTC299的抗COVID-19潜力，PTC299是一种口服有效的化合物，它是二氢乳清酸脱氢酶（DHODH）（从头嘧啶生物合成途径的限速酶）的有效抑制剂。在组织培养中，PTC299表现出对SARS CoV-2复制的强烈，剂量依赖性和DHODH依赖性抑制（EC50范围为2.0至31.6 nM），选择性指数> 3,800。PTC299还阻止了其他RNA病毒（包括埃博拉病毒）的复制。与已知的DHODH对免疫调节性细胞因子产生的要求一致，PTC299抑制白介素（IL）-6，IL-17A（也称为IL-17）的产生，IL-17F和组织培养模型中的血管内皮生长因子（VEGF）。抗SARS-CoV-2活性，细胞因子抑制活性以及先前建立的良好药代动力学和人体安全性相结合，使PTC299成为COVID-19的有前途的治疗方法。