Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention’s Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.

瑞德西韦是一种广谱抗病毒核苷酸前药，已在埃博拉病毒患者中进行了临床评估，最近获得了治疗 COVID-19 的紧急使用授权 (EUA)。经联邦选择药物计划和疾病控制与预防中心机构生物安全委员会的批准，我们通过在瑞德西韦选择下连续传代埃博拉病毒来表征瑞德西韦的耐药性特征；传代 35 代后，我们产生了对瑞德西韦敏感性低水平降低的谱系。我们发现埃博拉病毒聚合酶中的单个氨基酸取代 F548S 可导致对瑞德西韦的敏感性低水平降低。 F548 残基在丝状病毒中高度保守，但应在新型丝状病毒、持续爆发的新出现的变种以及接受瑞德西韦治疗的埃博拉病毒患者中进行特定监测。同源模型表明，埃博拉病毒聚合酶 F548 残基位于聚合酶活性位点的 F 基序中，该区域先前被认为对冠状病毒的耐药突变敏感。我们的数据表明，对接受瑞德西韦治疗的 COVID-19 患者的聚合酶这一区域进行分子监测也是有必要的。