From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability

The persistence of current outbreaks of Ebola virus (EBOV) disease and challenges in the production and administration of approved vaccines and treatments highlight the continuous exploration of new therapeutic alternatives. In this context, this work focuses on optimizing diarylsulfide hits previously identified as EBOV entry inhibitors. Structural modifications resulted in diarylamine derivatives, with confirmed antiviral activity against replicative EBOV and significantly improved metabolic stability compared to diarylsulfides. Using different techniques, the EBOV glycoprotein (EBOV-GP) was identified as the target of these compounds. Residue Y517GP2 is critical for biological activity, while T519GP2, E100GP1, and D522GP2 also contribute to ligand binding. Furthermore, the binding of the derivatives to EBOV-GP has been shown to destabilize the complex with the virus receptor NPC1. In short, a new family of diarylsulfides and diarylamines with antiviral activity against EBOV has been developed, and their mechanism of action has been deciphered, paving the way for future pharmaceutical development.

当前埃博拉病毒（Ebola virus, EBOV）疫情的持续存在，以及获批疫苗与治疗方案在生产、施用环节面临的诸多挑战，凸显了持续探索新型治疗替代策略的必要性。在此背景下，本研究聚焦于对此前被鉴定为埃博拉病毒进入抑制剂的二芳基硫（diarylsulfide）类命中化合物进行优化。经结构修饰后获得二芳基胺（diarylamine）衍生物，该衍生物对复制型埃博拉病毒展现出确切的抗病毒活性，且相较于二芳基硫类化合物，其代谢稳定性得到显著提升。通过多种实验技术，研究人员确认埃博拉病毒糖蛋白（EBOV-GP）为这类化合物的作用靶点。其中GP2亚基的残基Y517对生物活性至关重要，而GP2亚基的T519、GP1亚基的E100以及GP2亚基的D522同样参与配体结合过程。此外，实验证实该类衍生物与EBOV-GP的结合可破坏病毒受体NPC1与该糖蛋白所形成复合物的稳定性。简言之，本研究成功开发出一类具有抗埃博拉病毒活性的二芳基硫及二芳基胺新化合物家族，并阐明了其作用机制，为后续药物研发铺平了道路。