Liu Yan-Yun, Li Zheng-Ao, Zhou Yu-Zheng, Wang Sen-Lin, Chen Zong-Peng, Liu Si-Xu, Zhan Peng, Zhou Ying-Jun, Xia Zan-Xian, Deng Xu
Xiangya School of Pharmaceutical Science, Central South University, Changsha, 410013, Hunan, China.
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
Eur J Med Chem. 2025 Jun 5;290:117582. doi: 10.1016/j.ejmech.2025.117582. Epub 2025 Mar 29.
The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 (DNJ-3). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的全球新冠疫情凸显了开发新型广谱抗病毒药物以应对其高突变率和新出现变体的迫切需求。宿主内质网α-葡萄糖苷酶I/II是开发针对依赖内质网质量控制进行感染的病毒株的广谱抗病毒药物的有前景的宿主靶向治疗靶点。在此，我们设计并合成了一系列受中医理论启发的DNJ-黄酮类共轭物作为新型α-葡萄糖苷酶抑制剂，并在非复制性SARS-CoV-2假病毒（PsV）试验中对其体外抗病毒活性进行了筛选。值得注意的是，DNJ-20不仅对α-葡萄糖苷酶和病毒进入过程表现出显著的抑制活性，而且对SARS-CoV-2假病毒（PsV）、几种SARS-CoV-2变体以及人冠状病毒229E（HCoV-229E）和人冠状病毒OC43（HCoV-OC43）具有强效且广谱的抗冠状病毒活性，半数有效浓度（EC）值高达1.49 μM，比基准α-葡萄糖苷酶抑制剂UV-4（DNJ-3）更有效。此外，它在人宫颈癌细胞系HeLa-ACE2、人胚肾细胞系HEK-293T和人支气管上皮细胞系Beas-2B中没有可观察到的细胞毒性。因此，受中医理论启发的DNJ-黄酮类共轭物可作为有前景的药物先导物，用于泛冠状病毒治疗开发，以应对当前和未来的冠状病毒大流行。
