Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan; Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.
Antiviral Res. 2020 Nov;183:104932. doi: 10.1016/j.antiviral.2020.104932. Epub 2020 Sep 15.
Ebolaviruses and marburgviruses, members of the family Filoviridae, are known to cause fatal diseases often associated with hemorrhagic fever. Recent outbreaks of Ebola virus disease in West African countries and the Democratic Republic of the Congo have made clear the urgent need for the development of therapeutics and vaccines against filoviruses. Using replication-incompetent vesicular stomatitis virus (VSV) pseudotyped with the Ebola virus (EBOV) envelope glycoprotein (GP), we screened a chemical compound library to obtain new drug candidates that inhibit filoviral entry into target cells. We discovered a biaryl sulfonamide derivative that suppressed in vitro infection mediated by GPs derived from all known human-pathogenic filoviruses. To determine the inhibitory mechanism of the compound, we monitored each entry step (attachment, internalization, and membrane fusion) using lipophilic tracer-labeled ebolavirus-like particles and found that the compound efficiently blocked fusion between the viral envelope and the endosomal membrane during cellular entry. However, the compound did not block the interaction of GP with the Niemann-Pick C1 protein, which is believed to be the receptor of filoviruses. Using replication-competent VSVs pseudotyped with EBOV GP, we selected escape mutants and identified two EBOV GP amino acid residues (positions 47 and 66) important for the interaction with this compound. Interestingly, these amino acid residues were located at the base region of the GP trimer, suggesting that the compound might interfere with the GP conformational change required for membrane fusion. These results suggest that this biaryl sulfonamide derivative is a novel fusion inhibitor and a possible drug candidate for the development of a pan-filovirus therapeutic.
埃博拉病毒和马尔堡病毒属于丝状病毒科，已知会导致常伴有出血热的致命疾病。西非国家和刚果民主共和国最近爆发的埃博拉病毒病清楚地表明，迫切需要开发针对丝状病毒的治疗方法和疫苗。我们使用复制缺陷的水疱性口炎病毒（VSV）假型化埃博拉病毒（EBOV）包膜糖蛋白（GP），筛选了一个化学化合物文库，以获得抑制丝状病毒进入靶细胞的新药物候选物。我们发现了一种联苯磺酰胺衍生物，它抑制了来自所有已知人类致病性丝状病毒的 GP 介导的体外感染。为了确定该化合物的抑制机制，我们使用亲脂性示踪标记的埃博拉病毒样颗粒监测了每个进入步骤（附着、内化和膜融合），发现该化合物在细胞进入过程中有效地阻断了病毒包膜与内体膜之间的融合。然而，该化合物不阻断 GP 与尼曼-匹克 C1 蛋白的相互作用，而尼曼-匹克 C1 蛋白被认为是丝状病毒的受体。我们使用复制能力的 VSV 假型化 EBOV GP，选择逃逸突变体，并确定了两个 EBOV GP 氨基酸残基（位置 47 和 66）对于与该化合物的相互作用很重要。有趣的是，这些氨基酸残基位于 GP 三聚体的基部区域，表明该化合物可能干扰了膜融合所需的 GP 构象变化。这些结果表明，这种联苯磺酰胺衍生物是一种新型融合抑制剂，可能是开发泛丝状病毒治疗方法的候选药物。
