The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, exhibited an excellent anti-influenza activity (EC, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability ( = 71.60%). The prodrug demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that 's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.
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http://dx.doi.org/10.1021/acs.jmedchem.4c01979 | DOI Listing |
Fukushima J Med Sci
December 2024
Department of Pediatrics, Fukushima Medical University.
Since 2000, rapid antigen detection kits and anti-influenza drugs have been used for the early diagnosis and treatment of influenza in Japan, respectively. The main drugs available in clinical practice are the neuraminidase inhibitors oseltamivir, zanamivir, laninamivir, and peramivir, as well as the cap-dependent endonuclease inhibitor baloxavir marboxil. Antiviral therapy with neuraminidase inhibitors has been practiced for many years, especially in Japan; it can shorten the febrile period and reduce complications.
View Article and Find Full Text PDFJ Med Chem
December 2024
Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, exhibited an excellent anti-influenza activity (EC, H1N1 = 1.
View Article and Find Full Text PDFAdv Ther
December 2024
School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomita-machi, Koriyama, Fukushima, 963-8611, Japan.
Introduction: Vaccines can prevent influenza (flu) infections and are cost-effective for society and healthcare. However, the cost-effectiveness of post-exposure prophylaxis as a follow-up strategy is unclear. This study aims to evaluate the cost utility of post-exposure prophylaxis and treatment strategies with neuraminidase inhibitors and a cap-dependent endonuclease inhibitor for flu infections from the perspective of healthcare costs in Japan.
View Article and Find Full Text PDFPharmacotherapy
November 2024
Clinical and Administrative Pharmacy Sciences, College of Pharmacy, Howard University, Washington, DC, USA.
The avian influenza is a serious infection caused by influenza virus that is native to birds. Avian influenza remains a global challenge due to high transmission and mortality rates. The highly pathogenic strain of H5N1 resulted in significant outbreaks and deaths globally since the late 1800s.
View Article and Find Full Text PDFInt J Antimicrob Agents
November 2024
Clinical Pharmacology Research Centre, Huashan Hospital, Fudan University, Shanghai, China; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Antibiotic Clinical Pharmacology of the National Health and Commission, Shanghai, China; National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Research Ward of Huashan Hospital, Fudan University, Shanghai, China. Electronic address:
Background: We investigated the safety, tolerability, and pharmacokinetics of ZX-7101A tablets, a novel cap-dependent endonuclease inhibitor, in healthy participants in a first-in-human study.
Methods: The single ascending dose (SAD) part of the study included 40, 80, 160, 240, and 320 mg dose cohorts with10 participants in each dose cohort (8 participants received ZX-7101A tablets and 2 participants received placebo). The food effect (FE) part of the study was a randomised, 2-cycle, 2-way crossover design, which enrolled 16 participants to receive a single oral dose of 80 mg ZX-7101A tablets.
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