Zhao Jianyuan, Zhang Guoning, Li YaSheng, Ma Ling, Yi Dongrong, Li Quanjie, Shi Yu, Guo Saisai, Liu Tianfu, Wang Yujia, Li Xiaoyu, Wang Yucheng, Tan Wenjie, Li Jiabin, Cen Shan
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
Anhui Province Key Laboratory of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Eur J Med Chem. 2025 Apr 15;288:117422. doi: 10.1016/j.ejmech.2025.117422. Epub 2025 Feb 20.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of coronavirus disease (COVID-19) causing a pandemic with growing global transmission. The viral RNA-dependent RNA polymerase (RdRp) is conserved especially for variants of concern (VOCs), making it as an effective antivirals target. Due to the proofreading activity of coronavirus nsp14/nsp10, limited the efficacy of nucleoside analogs in vivo. Herein, we identified that Phenazopyridine hydrochloride (PAP) inhibits SARS-CoV-2 with EC of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC of 1.11 μmol/L. PAP and its derivatives can bind directly to SARS-CoV-2 RdRp, fully resistance to the exoribonuclease (ExoN) and exhibit broad spectrum anti-CoV activities. Combined with the current data available on the safe and pharmacokinetics of PAP as an approved drug in clinical use, these results provide a path for the urgently needed antivirals to combat SARS-CoV-2.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是冠状病毒病（COVID-19）的病原体，其在全球的传播日益增加，引发了大流行。病毒的RNA依赖性RNA聚合酶（RdRp）具有保守性，尤其是对于关注的变异株（VOCs），这使其成为一个有效的抗病毒靶点。由于冠状病毒nsp14/nsp10的校对活性，限制了核苷类似物在体内的疗效。在此，我们确定盐酸非那吡啶（PAP）对SARS-CoV-2具有抑制作用，半数有效浓度（EC）为5.37 μmol/L。此外，PAP能有效抑制SARS-CoV-2 RdRp，其EC值为7.37 μmol/L，经过进一步优化，化合物PAP-22表现出最具潜力的抑制作用，EC为1.11 μmol/L。PAP及其衍生物可直接与SARS-CoV-2 RdRp结合，对核酸外切酶（ExoN）完全耐药，并表现出广谱抗冠状病毒活性。结合目前关于PAP作为临床使用的已批准药物的安全性和药代动力学的现有数据，这些结果为对抗SARS-CoV-2急需的抗病毒药物提供了一条途径。
