tetano
Editor, Senior Moderator
J Med Chem
. 2024 Dec 10.
doi: 10.1021/acs.jmedchem.4c01979. Online ahead of print. Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment
Yongzhi Chen[SUP] 1 [/SUP], Kunyu Lu[SUP] 2 [/SUP], Binhao Rong[SUP] 2 [/SUP], Yuanmei Wen[SUP] 1 [/SUP], Guanguan Li[SUP] 3 [/SUP], Shuo Li[SUP] 1 [/SUP], Deyin Guo[SUP] 4 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Shuwen Liu[SUP] 2 5 [/SUP], Xumu Zhang[SUP] 1 [/SUP]
Affiliations
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, ATV2301 exhibited an excellent anti-influenza activity (EC[SUB]50[/SUB], H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 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.
. 2024 Dec 10.
doi: 10.1021/acs.jmedchem.4c01979. Online ahead of print. Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment
Yongzhi Chen[SUP] 1 [/SUP], Kunyu Lu[SUP] 2 [/SUP], Binhao Rong[SUP] 2 [/SUP], Yuanmei Wen[SUP] 1 [/SUP], Guanguan Li[SUP] 3 [/SUP], Shuo Li[SUP] 1 [/SUP], Deyin Guo[SUP] 4 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Shuwen Liu[SUP] 2 5 [/SUP], Xumu Zhang[SUP] 1 [/SUP]
Affiliations
- PMID: 39658517
- DOI: 10.1021/acs.jmedchem.4c01979
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, ATV2301 exhibited an excellent anti-influenza activity (EC[SUB]50[/SUB], H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 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.