tetano
Editor, Senior Moderator
Eur J Med Chem
. 2024 Feb 12:268:116232.
doi: 10.1016/j.ejmech.2024.116232. Online ahead of print. Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2
Nian-Dong Mao[SUP] 1 [/SUP], Yueying Xu[SUP] 2 [/SUP], Hao Che[SUP] 2 [/SUP], Xia Yao[SUP] 2 [/SUP], Yuan Gao[SUP] 3 [/SUP], Chenchen Wang[SUP] 4 [/SUP], Haowen Deng[SUP] 2 [/SUP], Zi Hui[SUP] 5 [/SUP], Hang Zhang[SUP] 6 [/SUP], Xiang-Yang Ye[SUP] 7 [/SUP]
Affiliations
Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the μ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC[SUB]50[/SUB] value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.
Keywords: AAK1; Antivirus; Clathrin-mediated endocytosis; Inhibitor.
. 2024 Feb 12:268:116232.
doi: 10.1016/j.ejmech.2024.116232. Online ahead of print. Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2
Nian-Dong Mao[SUP] 1 [/SUP], Yueying Xu[SUP] 2 [/SUP], Hao Che[SUP] 2 [/SUP], Xia Yao[SUP] 2 [/SUP], Yuan Gao[SUP] 3 [/SUP], Chenchen Wang[SUP] 4 [/SUP], Haowen Deng[SUP] 2 [/SUP], Zi Hui[SUP] 5 [/SUP], Hang Zhang[SUP] 6 [/SUP], Xiang-Yang Ye[SUP] 7 [/SUP]
Affiliations
- PMID: 38377825
- DOI: 10.1016/j.ejmech.2024.116232
Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the μ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC[SUB]50[/SUB] value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.
Keywords: AAK1; Antivirus; Clathrin-mediated endocytosis; Inhibitor.