Lu Jiani, He Yingying, Li Yaqi, Chen Xixiang, Li Hongtao, Chen Xuwen, Xu Jianrong, Chen Hongzhuan, Wang Ying, He Xiao, Liu Shunying, Chen Lili
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Int J Biol Macromol. 2025 Jan;287:138529. doi: 10.1016/j.ijbiomac.2024.138529. Epub 2024 Dec 7.
As new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, they raise increasing concerns about the efficacy of neutralizing antibodies and vaccines. This situation underscores the urgent need for specific drugs against the coronavirus disease 2019 (COVID-19). Given that COVID-19 is particularly associated with substantial inflammation, the development of novel, effective antiviral and anti-inflammatory agents represents a promising research direction. In this study, we virtually screened a library consisting of 2900 anti-inflammatory small molecules for their inhibitory effects on the 3-chymotrypsin-like protease (3CL) of SARS-CoV-2 and selected 23 promising candidates for further testing using a fluorescence resonance energy transfer (FRET) assay. The results indicated that Gnetol had the most potent inhibitory effect against SARS-CoV-2 3CL. Further structural modifications led to the identification of compounds 38 and 39, which displayed superior inhibitory activity. Compound 39 showed good selectivity for host proteases. Subsequently, Gnetol and its structural analogs, which demonstrated SARS-CoV-2 3CL inhibitory activity, were tested for their anti-inflammatory effects. Among these, Piceatannol and compound 39 exhibited enhanced anti-inflammatory effects, with compound 39 alone showing the most potent antiviral and anti-inflammatory activity. Thus, our study has explored a new research strategy for discovering antiviral and anti-inflammatory bifunctional molecules. The discovery of Gnetol and its structural analogs has provided new lead candidates for the development of COVID-19 therapeutics.
随着严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新变种不断出现，它们引发了人们对中和抗体和疫苗效力日益增加的担忧。这种情况凸显了对抗2019冠状病毒病（COVID-19）的特定药物的迫切需求。鉴于COVID-19特别与大量炎症相关，开发新型、有效的抗病毒和抗炎药物代表了一个有前景的研究方向。在本研究中，我们虚拟筛选了一个由2900种抗炎小分子组成的文库，以研究它们对SARS-CoV-2的3-糜蛋白酶样蛋白酶（3CL）的抑制作用，并使用荧光共振能量转移（FRET）测定法选择了23种有前景的候选物进行进一步测试。结果表明，去甲二氢愈创木酸对SARS-CoV-2 3CL具有最有效的抑制作用。进一步的结构修饰导致鉴定出化合物38和39，它们表现出优异的抑制活性。化合物39对宿主蛋白酶显示出良好的选择性。随后，对表现出SARS-CoV-2 3CL抑制活性的去甲二氢愈创木酸及其结构类似物进行了抗炎作用测试。其中，白藜芦醇和化合物39表现出增强的抗炎作用，仅化合物39显示出最有效的抗病毒和抗炎活性。因此，我们的研究探索了一种发现抗病毒和抗炎双功能分子的新研究策略。去甲二氢愈创木酸及其结构类似物的发现为COVID-19治疗药物的开发提供了新的先导候选物。
