Chen Xiaoxin, Ma Qinhai, Zhao Manyu, Yao Yuqin, Zhang Qianru, Liu Miao, Yang Zifeng, Deng Wenbin
School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China.
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.
Pharmaceuticals (Basel). 2023 Feb 27;16(3):365. doi: 10.3390/ph16030365.
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 (IC value), which was better than that of the clinical candidate compound VX-787 with the same target. In vitro, the EC 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.
甲型流感病毒具有高度传染性，常常引发全球大流行。对已获批药物耐药的甲型流感病毒毒株的流行，是当前甲型流感临床治疗面临的巨大挑战。RNA聚合酶是甲型流感病毒复制中的关键酶，是抗甲型流感治疗的一个有前景的靶点。在本文中，我们报道了一种新型强效抗甲型流感病毒抑制剂ZSP1273，其靶向甲型流感病毒RNA聚合酶，尤其针对多重耐药毒株。ZSP1273对RNA聚合酶活性的抑制活性为0.562±0.116 nM（IC值），优于具有相同靶点的临床候选化合物VX-787。在体外，ZSP1273对正常甲型流感病毒毒株（即H1N1和H3N2）的EC值在0.01 nM至0.063 nM之间，优于已获许可的药物奥司他韦。此外，对奥司他韦耐药的毒株、巴洛沙韦耐药的毒株以及高致病性禽流感毒株对ZSP1273也敏感。在体内，ZSP1273在小鼠模型中以剂量依赖性方式有效降低甲型流感病毒滴度，并使小鼠保持高存活率。此外，在雪貂模型中也观察到了ZSP1273对甲型流感病毒感染的抑制活性。药代动力学研究表明，ZSP1273在小鼠、大鼠和比格犬单剂量和连续多剂量给药后具有良好的药代动力学特征。总之，ZSP1273是一种高效的抗甲型流感病毒复制抑制剂，尤其对多重耐药毒株有效。ZSP1273目前正在进行III期临床试验。
