tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Sep 29:261:115845.
doi: 10.1016/j.ejmech.2023.115845. Online ahead of print. Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors
Chuanfeng Liu[SUP] 1 [/SUP], Ying Zhang[SUP] 2 [/SUP], Ping Li[SUP] 3 [/SUP], Huinan Jia[SUP] 2 [/SUP], Han Ju[SUP] 2 [/SUP], Jiwei Zhang[SUP] 2 [/SUP], Edeildo Ferreira da Silva-Júnior[SUP] 4 [/SUP], Sunanda Samanta[SUP] 5 [/SUP], Parimal Kar[SUP] 6 [/SUP], Bing Huang[SUP] 7 [/SUP], Xinyong Liu[SUP] 8 [/SUP], Peng Zhan[SUP] 9 [/SUP]
Affiliations
Concerning the emergence of resistance to current anti-influenza drugs, our previous phenotypic-based screening study identified the compound A9 as a promising lead compound. This chalcone analog, containing a 2,6-dimethoxyphenyl moiety, exhibited significant inhibitory activity against oseltamivir-resistant strains (H1N1 pdm09), with an EC[SUB]50[/SUB] value of 1.34 μM. However, it also displayed notable cytotoxicity, with a CC[SUB]50[/SUB] value of 41.46 μM. Therefore, compound A9 was selected as a prototype structure for further structural optimization in this study. Initially, it was confirmed that the substituting the α,β-unsaturated ketone with pent-1,4-diene-3-one as a linker group significantly reduced the cytotoxicity of the final compounds. Subsequently, the penta-1,4-dien-3-one group was utilized as a privileged fragment for further structural optimization. Following two subsequent rounds of optimizations, we identified compound IIB-2, which contains a 2,6-dimethoxyphenyl- and 1,4-pentadiene-3-one moieties. This compound exhibited inhibitory effects on oseltamivir-resistant strains comparable to its precursor (compound A9), while demonstrating reduced toxicity (CC[SUB]50[/SUB] > 100 μM). Furthermore, we investigated its mechanism of action against anti-influenza virus through immunofluorescence, Western blot, and surface plasmon resonance (SPR) experiments. The results revealed that compound IIB-2 can impede virus proliferation by blocking the export of influenza virus nucleoprotein. Thusly, our findings further emphasize influenza nuclear export as a viable target for designing novel chalcone-like derivatives with potential inhibitory properties that could be explored in future lead optimization studies.
Keywords: Anti-influenza; Influenza virus; MM/PBSA; Nucleoprotein; Ribonucleoprotein complex; SPR.
. 2023 Sep 29:261:115845.
doi: 10.1016/j.ejmech.2023.115845. Online ahead of print. Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors
Chuanfeng Liu[SUP] 1 [/SUP], Ying Zhang[SUP] 2 [/SUP], Ping Li[SUP] 3 [/SUP], Huinan Jia[SUP] 2 [/SUP], Han Ju[SUP] 2 [/SUP], Jiwei Zhang[SUP] 2 [/SUP], Edeildo Ferreira da Silva-Júnior[SUP] 4 [/SUP], Sunanda Samanta[SUP] 5 [/SUP], Parimal Kar[SUP] 6 [/SUP], Bing Huang[SUP] 7 [/SUP], Xinyong Liu[SUP] 8 [/SUP], Peng Zhan[SUP] 9 [/SUP]
Affiliations
- PMID: 37804770
- DOI: 10.1016/j.ejmech.2023.115845
Concerning the emergence of resistance to current anti-influenza drugs, our previous phenotypic-based screening study identified the compound A9 as a promising lead compound. This chalcone analog, containing a 2,6-dimethoxyphenyl moiety, exhibited significant inhibitory activity against oseltamivir-resistant strains (H1N1 pdm09), with an EC[SUB]50[/SUB] value of 1.34 μM. However, it also displayed notable cytotoxicity, with a CC[SUB]50[/SUB] value of 41.46 μM. Therefore, compound A9 was selected as a prototype structure for further structural optimization in this study. Initially, it was confirmed that the substituting the α,β-unsaturated ketone with pent-1,4-diene-3-one as a linker group significantly reduced the cytotoxicity of the final compounds. Subsequently, the penta-1,4-dien-3-one group was utilized as a privileged fragment for further structural optimization. Following two subsequent rounds of optimizations, we identified compound IIB-2, which contains a 2,6-dimethoxyphenyl- and 1,4-pentadiene-3-one moieties. This compound exhibited inhibitory effects on oseltamivir-resistant strains comparable to its precursor (compound A9), while demonstrating reduced toxicity (CC[SUB]50[/SUB] > 100 μM). Furthermore, we investigated its mechanism of action against anti-influenza virus through immunofluorescence, Western blot, and surface plasmon resonance (SPR) experiments. The results revealed that compound IIB-2 can impede virus proliferation by blocking the export of influenza virus nucleoprotein. Thusly, our findings further emphasize influenza nuclear export as a viable target for designing novel chalcone-like derivatives with potential inhibitory properties that could be explored in future lead optimization studies.
Keywords: Anti-influenza; Influenza virus; MM/PBSA; Nucleoprotein; Ribonucleoprotein complex; SPR.