Liao En-You, Chou Shen-Chieh, Huang Tzu-Yu, Huang Sheng-Cih, Yu Teng-Kai, Chou Feng-Pai, Wu Tung-Kung
Department of Biological Science and Technology, National Yang Ming Chiao Tung University 75 Po-Ai Street Hsinchu 30010 Taiwan Republic of China
Center for Emergent Functional Matter Science, National Yang Ming Chiao Tung University 1001 Ta-Hsueh Rd Hsinchu 30010 Taiwan Republic of China.
RSC Adv. 2025 Sep 11;15(39):32871-32881. doi: 10.1039/d5ra04664e. eCollection 2025 Sep 5.
The SARS-CoV-2 main protease (M) is a validated antiviral target for COVID-19 therapeutics due to its essential role in viral replication and absence of human homologs. Here, we report the synthesis and characterization of glycosylated 18β-glycyrrhetinic acid (18β-GA) derivatives using a one-pot, four-enzyme system to improve drug-like properties and antiviral efficacy. Among the derivatives, 18β-GA-3--β-Glc and 18β-GA-30--β-Glc exhibited promising M inhibition, with IC values of 8.70 ± 0.80 μM and 4.77 ± 0.49 μM, respectively. Biolayer interferometry revealed favorable binding affinities and reversible interactions with M, while molecular docking demonstrated their stable binding conformations resembling that of GC376. These glycosides also showed improved predicted oral bioavailability and physicochemical profiles. Our findings support the potential of glycosylated 18β-GA derivatives as cost-effective and scalable antiviral candidates targeting SARS-CoV-2 M.
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）主要蛋白酶（M）因其在病毒复制中的关键作用且不存在人类同源物，而成为治疗2019冠状病毒病（COVID-19）的有效抗病毒靶点。在此，我们报告了使用一锅四酶系统合成并表征糖基化18β-甘草次酸（18β-GA）衍生物，以改善其类药物性质和抗病毒功效。在这些衍生物中，18β-GA-3--β-Glc和18β-GA-30--β-Glc表现出有前景的M抑制活性，其半数抑制浓度（IC）值分别为8.70±0.80μM和4.77±0.49μM。生物层干涉术显示它们与M具有良好的结合亲和力和可逆相互作用，而分子对接表明它们的稳定结合构象类似于GC376。这些糖苷还显示出预测的口服生物利用度和理化性质有所改善。我们的研究结果支持糖基化18β-GA衍生物作为靶向SARS-CoV-2 M的具有成本效益且可扩展的抗病毒候选药物的潜力。
