tetano
Editor, Senior Moderator
J Med Chem
. 2025 Jun 18.
doi: 10.1021/acs.jmedchem.5c00042. Online ahead of print. Design and Synthesis of PA[SUB]N[/SUB] Endonuclease Inhibitors through Spirocyclization Strategy against Influenza A Virus
Shuangrong Liu[SUP] 1 [/SUP], Yuting Li[SUP] 2 3 [/SUP], Bo Peng[SUP] 1 [/SUP], Shaokai Ni[SUP] 2 [/SUP], Shuaiyi Wang[SUP] 2 [/SUP], Qi Zhu[SUP] 2 [/SUP], Haifeng Li[SUP] 2 [/SUP], Qian Yang[SUP] 4 [/SUP], Hui Zhang[SUP] 1 [/SUP], Peichen Pan[SUP] 1 [/SUP], Jiayi Lin[SUP] 2 [/SUP], Yongping Yu[SUP] 1 5 [/SUP], Zeli Zhang[SUP] 4 [/SUP], Yushen Du[SUP] 2 [/SUP], Wenteng Chen[SUP] 1 5 [/SUP]
Affiliations
The PA[SUB]N[/SUB] endonuclease inhibitor baloxavir marked a significant advancement in influenza treatment. Herein, we reported the development of PA[SUB]N[/SUB] inhibitors through structural simplification of baloxavir̀s tricyclic system coupled with strategic incorporation of a spirocyclic architecture, which aims to construct a new metal-binding pharmacophore with distinct three-dimensional features. Lead 39-(S) was identified and exhibited nanomolar potency against influenza virus polymerase complexes (IC[SUB]50[/SUB] = 17.4 nM), which was mechanistically attributed to PA[SUB]N[/SUB] endonuclease inhibition. Furthermore, 39-(S) demonstrated robust antiviral activities against multiple current and different influenza virus strains while showing minimal cytotoxicity in MDCK cells, ensuring an exceptional selectivity index of more than 2.4 × 10[SUP]5[/SUP] during antiviral treatment. Additionally, both 39-(S) and its prodrug 41 significantly suppressed viral replication in an A/WSN/33 infected mouse model with efficacy profiles remarkably comparable to those of baloxavir. Collectively, 39-(S) emerges as a potent PA[SUB]N[/SUB] inhibitor with the potential for further development.
. 2025 Jun 18.
doi: 10.1021/acs.jmedchem.5c00042. Online ahead of print. Design and Synthesis of PA[SUB]N[/SUB] Endonuclease Inhibitors through Spirocyclization Strategy against Influenza A Virus
Shuangrong Liu[SUP] 1 [/SUP], Yuting Li[SUP] 2 3 [/SUP], Bo Peng[SUP] 1 [/SUP], Shaokai Ni[SUP] 2 [/SUP], Shuaiyi Wang[SUP] 2 [/SUP], Qi Zhu[SUP] 2 [/SUP], Haifeng Li[SUP] 2 [/SUP], Qian Yang[SUP] 4 [/SUP], Hui Zhang[SUP] 1 [/SUP], Peichen Pan[SUP] 1 [/SUP], Jiayi Lin[SUP] 2 [/SUP], Yongping Yu[SUP] 1 5 [/SUP], Zeli Zhang[SUP] 4 [/SUP], Yushen Du[SUP] 2 [/SUP], Wenteng Chen[SUP] 1 5 [/SUP]
Affiliations
- PMID: 40533885
- DOI: 10.1021/acs.jmedchem.5c00042
The PA[SUB]N[/SUB] endonuclease inhibitor baloxavir marked a significant advancement in influenza treatment. Herein, we reported the development of PA[SUB]N[/SUB] inhibitors through structural simplification of baloxavir̀s tricyclic system coupled with strategic incorporation of a spirocyclic architecture, which aims to construct a new metal-binding pharmacophore with distinct three-dimensional features. Lead 39-(S) was identified and exhibited nanomolar potency against influenza virus polymerase complexes (IC[SUB]50[/SUB] = 17.4 nM), which was mechanistically attributed to PA[SUB]N[/SUB] endonuclease inhibition. Furthermore, 39-(S) demonstrated robust antiviral activities against multiple current and different influenza virus strains while showing minimal cytotoxicity in MDCK cells, ensuring an exceptional selectivity index of more than 2.4 × 10[SUP]5[/SUP] during antiviral treatment. Additionally, both 39-(S) and its prodrug 41 significantly suppressed viral replication in an A/WSN/33 infected mouse model with efficacy profiles remarkably comparable to those of baloxavir. Collectively, 39-(S) emerges as a potent PA[SUB]N[/SUB] inhibitor with the potential for further development.