Univ Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
APTEEUS, Campus Pasteur Lille, Lille, France.
PLoS Pathog. 2022 May 19;18(5):e1010498. doi: 10.1371/journal.ppat.1010498. eCollection 2022 May.
Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.
药物重定位具有缩短监管临床前开发步骤的优势。在这里，我们筛选了已经在一个或多个地理区域注册的药物化合物库，以鉴定出对 SARS-CoV-2 具有相关效力的抗病毒活性的化合物。在测试的 1942 种化合物中，有 21 种在 Vero-81 细胞中表现出显著的抗病毒活性。其中，氯氧酚，一种用于治疗细菌呼吸道感染的抗菌药物，由于其良好的安全性和药代动力学特性，进一步被研究。值得注意的是，氯氧酚在人肺中可达到的峰值浓度是其在人肺细胞中对 SARS-CoV-2 的 IC50 的 20 多倍。该化合物在进入后阶段抑制 SARS-CoV-2。最后，对人 ACE2 受体转基因小鼠的治疗性治疗降低了病毒载量，减少了炎症基因的表达，并降低了肺部病理学。总之，这些数据强烈支持氯氧酚作为治疗 COVID-19 患者的治疗候选药物。
