Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Eur J Med Chem. 2021 Apr 5;215:113242. doi: 10.1016/j.ejmech.2021.113242. Epub 2021 Feb 8.
Currently, SARS-CoV-2 virus is an emerging pathogen that has posed a serious threat to public health worldwide. However, no agents have been approved to treat SARS-CoV-2 infections to date, underscoring the great need for effective and practical therapies for SARS-CoV-2 outbreaks. We reported that a focused screen of OA saponins identified 3-O-β-chacotriosyl OA benzyl ester 2 as a novel small molecule inhibitor of SARS-CoV-2 virus entry, via binding to SARS-CoV-2 glycoprotein (S). We performed structure-activity relationship profiling of 2 and discovered C-17-COOH of OA was an important modification site that improved both inhibitor potency toward SARS-CoV-2 and selectivity index. Then optimization from hit to lead resulted in a potent fusion inhibitor 12f displaying strong inhibition against infectious SARS-CoV-2 with an IC value of 0.97 μM in vitro. Mechanism studies confirmed that inhibition of SARS-CoV-2 viral entry of 12f was mediated by the direct interaction with SARS-CoV-2 S2 subunit to block membrane fusion. These 3-O-β-chacotriosyl OA amide saponins are suitable for further optimization as SARS-CoV-2 entry inhibitors with the potential to be developed as therapeutic agents for the treatment of SARS-CoV-2 virus infections.
目前，SARS-CoV-2 病毒是一种新兴病原体，对全球公共卫生构成了严重威胁。然而，迄今为止，尚无针对 SARS-CoV-2 感染的批准药物，这凸显了迫切需要针对 SARS-CoV-2 爆发的有效和实用疗法。我们报告说，对 OA 皂苷的靶向筛选鉴定出 3-O-β-岩藻三糖 OA 苄酯 2 是一种新型的 SARS-CoV-2 病毒进入的小分子抑制剂，通过与 SARS-CoV-2 糖蛋白 (S) 结合。我们对 2 进行了构效关系分析，并发现 OA 的 C-17-COOH 是一个重要的修饰位点，可提高对 SARS-CoV-2 的抑制剂效力和选择性指数。然后从命中化合物到先导化合物的优化得到了一种有效的融合抑制剂 12f，在体外显示出对感染性 SARS-CoV-2 的强烈抑制作用，IC 值为 0.97 μM。机制研究证实，12f 抑制 SARS-CoV-2 病毒进入是通过与 SARS-CoV-2 S2 亚基的直接相互作用来阻断膜融合介导的。这些 3-O-β-岩藻三糖 OA 酰胺皂苷适合进一步优化，作为 SARS-CoV-2 进入抑制剂，有可能开发为治疗 SARS-CoV-2 病毒感染的治疗药物。
