2. Academic Validation
  3. Preclinical Study of ZSP1273, a Potent Antiviral Inhibitor of Cap Binding to the PB2 Subunit of Influenza A Polymerase

Preclinical Study of ZSP1273, a Potent Antiviral Inhibitor of Cap Binding to the PB2 Subunit of Influenza A Polymerase

  • Pharmaceuticals (Basel). 2023 Feb 27;16(3):365. doi: 10.3390/ph16030365.
Xiaoxin Chen 1,  Qinhai Ma 2,  Manyu Zhao 3,  Yuqin Yao 3,  Qianru Zhang 4,  Miao Liu 3,  Zifeng Yang 2,  Wenbin Deng 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China.
  • 2 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510030, China.
  • 3 Molecular Toxicology Laboratory of Sichuan Provincial Education Office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 36986465 DOI: 10.3390/ph16030365
Abstract

The influenza A virus is highly contagious and often causes global pandemics. The prevalence of strains of the influenza A virus that are resistant to approved drugs is a huge challenge for the current clinical treatment of influenza A. RNA polymerase is a pivotal enzyme in the replication of the influenza A virus, and it is a promising target for anti-influenza A therapies. In this paper, we report a novel and potent anti-influenza-A-virus inhibitor, ZSP1273, targeting the influenza A virus RNA polymerase, especially for multidrug-resistant strains. The inhibitory activity of ZSP1273 on RNA polymerase activity was 0.562 ± 0.116 nM (IC50 value), which was better than that of the clinical candidate compound VX-787 with the same target. In vitro, the EC50 values of ZSP1273 on normal influenza A virus strains (i.e., H1N1 and H3N2) varied from 0.01 nM to 0.063 nM, which were better than those of the licensed drug oseltamivir. Moreover, oseltamivir-resistant strains, baloxavir-resistant strains, and highly pathogenic avian influenza strains were also sensitive to ZSP1273. In vivo, ZSP1273 effectively reduced influenza A virus titers in a dose-dependent manner in a murine model and maintained a high survival rate in mice. In addition, the inhibitory activity of ZSP1273 on influenza A virus Infection was also observed in a ferret model. Pharmacokinetic studies showed the favorable pharmacokinetic characteristics of ZSP1273 in mice, rats, and beagle dogs after single-dose and continuous multiple-dose administration. In conclusion, ZSP1273 is a highly effective anti-influenza A virus replication inhibitor, especially against multidrug-resistant strains. ZSP1273 is currently being studied in phase III clinical trials.

Keywords

RNA polymerase; ZSP1273; antiviral drug; influenza A; influenza A virus.

Figures
Products