2. Academic Validation
  3. Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors

Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors

  • Eur J Med Chem. 2025 Apr 15:288:117422. doi: 10.1016/j.ejmech.2025.117422.
Jianyuan Zhao 1,  Guoning Zhang 1,  YaSheng Li 2,  Ling Ma 1,  Dongrong Yi 1,  Quanjie Li 1,  Yu Shi 1,  Saisai Guo 1,  Tianfu Liu 1,  Yujia Wang 1,  Xiaoyu Li 1,  Yucheng Wang 3,  Wenjie Tan 4,  Jiabin Li 5,  Shan Cen 6
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • 2 Anhui Province Key Laboratory of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: wangyucheng@imb.pumc.edu.cn.
  • 4 MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China. Electronic address: tanwj@ivdc.chinacdc.cn.
  • 5 Anhui Province Key Laboratory of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: lijiabin@ahmu.edu.cn.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: shancen@imb.pumc.edu.cn.
PMID: 39999742 DOI: 10.1016/j.ejmech.2025.117422
Abstract

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 EC50 of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC50 value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC50 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.

Keywords

COVID-19; Phenazopyridine hydrochloride; RdRp inhibitor; SARS-CoV-2; Structure-activity relationships; Synthesis.

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