{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:59:23Z","timestamp":1789181963875,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Province Key Area R&amp;D Program","award":["20198020201001"],"award-info":[{"award-number":["20198020201001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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 \u00b1 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.<\/jats:p>","DOI":"10.3390\/ph16030365","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T02:28:09Z","timestamp":1677551289000},"page":"365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Preclinical Study of ZSP1273, a Potent Antiviral Inhibitor of Cap Binding to the PB2 Subunit of Influenza A Polymerase"],"prefix":"10.3390","volume":"16","author":[{"given":"Xiaoxin","family":"Chen","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinhai","family":"Ma","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2097-6978","authenticated-orcid":false,"given":"Yuqin","family":"Yao","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianru","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifeng","family":"Yang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8897-4891","authenticated-orcid":false,"given":"Wenbin","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.4065\/mcp.2009.0588","article-title":"2009 H1N1 influenza","volume":"85","author":"Sullivan","year":"2010","journal-title":"Mayo Clin. 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