Ebola virus (EBOV) is an enveloped negative-sense, single-stranded RNA virus of the filovirus family that causes severe disease in humans. Approved therapies for EBOV disease are lacking. EBOV RNA synthesis is carried out by a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are therefore potential antiviral targets. To identify potential lead inhibitors of EBOV RNA synthesis, a library of small molecule compounds was screened against a previously established assay of EBOV RNA synthesis, the EBOV minigenome assay (MGA), in 384 well microplate format. The screen identified 56 hits that inhibited EBOV MGA activity by more than 70% while exhibiting less than 20% cell cytotoxicity. Inhibitory chemical scaffolds included angelicin derivatives, derivatives of the antiviral compound GSK983 and benzoquinolines. Structure-activity relationship (SAR) studies of the benzoquinoline scaffold produced ∼50 analogs and led to identification of an optimized compound, SW456, with a submicromolar IC₅₀ in the EBOV MGA and antiviral activity against infectious EBOV in cell culture. The compound was also active against a MGA for another deadly filovirus, Marburg virus. It also exhibited antiviral activity towards a negative-sense RNA virus from the rhabdovirus family, vesicular stomatitis virus, and a positive-sense RNA virus, Zika virus. Overall, these data demonstrate the potential of the EBOV MGA to identify anti-EBOV compounds and identifies the benzoquinoline series as a broad-spectrum antiviral lead.

埃博拉病毒（EBOV）是丝状病毒家族的一种包膜负义单链RNA病毒，可导致人类严重疾病。缺乏批准的EBOV疾病疗法。EBOV RNA合成是通过病毒编码的复合物进行的，该复合物具有病毒繁殖所需的RNA依赖性RNA聚合酶活性。因此，这种复合物及其活性是潜在的抗病毒靶标。为了识别EBOV RNA合成的潜在先导抑制剂，针对384孔微孔板格式的EBOV RNA合成先前确定的测定（EBOV微型基因组测定（MGA））筛选了小分子化合物库。该筛查确定了56个命中，这些命中抑制EBOV MGA活性超过70％，而细胞毒性却不到20％。抑制性化学支架包括当归衍生物，抗病毒化合物GSK983和苯并喹啉的衍生物。对苯并喹啉骨架的结构-活性关系（SAR）研究产生了约50个类似物，并通过亚微摩尔IC鉴定了优化的化合物SW456。在EBOV MGA中具有₅₀的抗性，并且在细胞培养中具有抗感染性EBOV的抗病毒活性。该化合物对另一种致命的丝状病毒，马尔堡病毒，也具有抗MGA的活性。它还对弹状病毒家族的阴性RNA病毒水泡性口炎病毒和阳性RNA病毒Zika病毒表现出抗病毒活性。总体而言，这些数据证明了EBOV MGA识别抗EBOV化合物的潜力，并将苯并喹啉系列确定为广谱抗病毒药。