Filoviruses, consisting of Ebola virus, Marburg virus and Cuevavirus, cause severe hemorrhagic fevers in humans with high mortality rates up to 90%. Currently, there is no approved vaccine or therapy available for the prevention and treatment of filovirus infection in humans. The recent 2013–2015 West African Ebola epidemic underscores the urgency to develop antiviral therapeutics against these infectious diseases. Our previous study showed that GPCR antagonists, particularly histamine receptor antagonists (antihistamines) inhibit Ebola and Marburg virus entry. In this study, we screened a library of 1220 small molecules with predicted antihistamine activity, identified multiple compounds with potent inhibitory activity against entry of both Ebola and Marburg viruses in human cancer cell lines, and confirmed their anti-Ebola activity in human primary cells. These small molecules target a late-stage of Ebola virus entry. Further structure-activity relationship studies around one compound (cp19) reveal the importance of the coumarin fused ring structure, especially the hydrophobic substituents at positions 3 and/or 4, for its antiviral activity, and this identified scaffold represents a favorable starting point for the rapid development of anti-filovirus therapeutic agents.

包括埃博拉病毒，马尔堡病毒和Cueva病毒在内的丝状病毒可引起严重的出血热，死亡率高达90％。当前，没有批准的疫苗或疗法可用于预防和治疗人类丝状病毒感染。最近的2013-2015年西非埃博拉疫情强调了开发针对这些传染病的抗病毒治疗剂的紧迫性。我们以前的研究表明，GPCR拮抗剂，尤其是组胺受体拮抗剂（抗组胺药）可以抑制埃博拉和马尔堡病毒的进入。在这项研究中，我们筛选了一个具有预测的抗组胺活性的1220个小分子文库，鉴定了多种具有有效抑制活性的化合物，这些化合物对人类癌细胞系中的埃博拉病毒和马尔堡病毒均具有抑制作用，并确认了它们在人类原代细胞中的抗埃博拉病毒活性。这些小分子靶向埃博拉病毒进入后期。围绕一种化合物（cp19）进行的进一步的结构-活性关系研究表明，香豆素稠合的环结构，特别是位置3和/或4处的疏水取代基对于其抗病毒活性很重要，这种鉴定出的支架代表了其良好的起点。抗丝状病毒治疗剂的快速发展。