tetano
Editor, Senior Moderator
Eur J Med Chem
. 2025 Feb 20:288:117422.
doi: 10.1016/j.ejmech.2025.117422. Online ahead of print. Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors
Jianyuan Zhao[SUP] 1 [/SUP], Guoning Zhang[SUP] 1 [/SUP], YaSheng Li[SUP] 2 [/SUP], Ling Ma[SUP] 1 [/SUP], Dongrong Yi[SUP] 1 [/SUP], Quanjie Li[SUP] 1 [/SUP], Yu Shi[SUP] 1 [/SUP], Saisai Guo[SUP] 1 [/SUP], Tianfu Liu[SUP] 1 [/SUP], Yujia Wang[SUP] 1 [/SUP], Xiaoyu Li[SUP] 1 [/SUP], Yucheng Wang[SUP] 3 [/SUP], Wenjie Tan[SUP] 4 [/SUP], Jiabin Li[SUP] 5 [/SUP], Shan Cen[SUP] 6 [/SUP]
Affiliations
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[SUB]50[/SUB] of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC[SUB]50[/SUB] value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC[SUB]50[/SUB] 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.
. 2025 Feb 20:288:117422.
doi: 10.1016/j.ejmech.2025.117422. Online ahead of print. Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors
Jianyuan Zhao[SUP] 1 [/SUP], Guoning Zhang[SUP] 1 [/SUP], YaSheng Li[SUP] 2 [/SUP], Ling Ma[SUP] 1 [/SUP], Dongrong Yi[SUP] 1 [/SUP], Quanjie Li[SUP] 1 [/SUP], Yu Shi[SUP] 1 [/SUP], Saisai Guo[SUP] 1 [/SUP], Tianfu Liu[SUP] 1 [/SUP], Yujia Wang[SUP] 1 [/SUP], Xiaoyu Li[SUP] 1 [/SUP], Yucheng Wang[SUP] 3 [/SUP], Wenjie Tan[SUP] 4 [/SUP], Jiabin Li[SUP] 5 [/SUP], Shan Cen[SUP] 6 [/SUP]
Affiliations
- PMID: 39999742
- DOI: 10.1016/j.ejmech.2025.117422
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[SUB]50[/SUB] of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC[SUB]50[/SUB] value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC[SUB]50[/SUB] 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.