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.

2019 年冠状病毒病 (COVID-19) 大流行迫切需要抑制 SARS-COV-2 病毒并抑制晚期疾病的暴发性炎症特征的治疗方法。在这里，我们描述了 PTC299 的抗 COVID-19 潜力，PTC299 是一种口服生物可利用的化合物，是二氢乳清酸脱氢酶 (DHODH) 的有效抑制剂，DHODH 是从头嘧啶核苷酸生物合成途径的限速酶。在组织培养中，PTC299 对 SARS−COV-2 复制表现出强大的、剂量依赖性和 DHODH 依赖性抑制作用（EC ₅₀范围，2.0–31.6 nM），选择性指数 >3,800。 PTC299还阻止其他RNA病毒的复制，包括埃博拉病毒。与免疫调节细胞因子产生的已知 DHODH 要求一致，PTC299 在组织培养模型中抑制白细胞介素 (IL)-6、IL-17A（也称为 IL-17）、IL-17 F 和血管内皮生长因子 (VEGF) 的产生。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特征相结合，使 PTC299 成为一种有前景的 COVID-19 治疗药物。