Department of Pediatrics, Division of Infectious Disease, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Coppe Healthcare Solutions, Waukesha, Wisconsin 53186, United States.
ACS Infect Dis. 2021 Jul 9;7(7):1985-1995. doi: 10.1021/acsinfecdis.1c00053. Epub 2021 Mar 30.
As the toll of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues, efforts are ongoing to identify new agents and repurpose safe drugs for its treatment. Antimalarial peroxides have reported antiviral and anticancer activities. Here, we evaluated the activities of artesunate (AS) and two ozonides (OZ418 and OZ277) against human α-coronavirus NL63 and β-coronaviruses OC43 and SARS-CoV-2 in several cell lines. OZ418 had the best selectivity index (SI) in NL63-infected Vero cells and MK2 cells. The overall SI of the tested compounds was cell-type dependent. In OC43-infected human foreskin fibroblasts, AS had the best cell-associated SI, ≥17 μM, while the SI of OZ418 and OZ277 was ≥12 μM and ≥7 μM, respectively. AS did not inhibit SARS-CoV-2 in either Vero or Calu-3 cells. A comparison of OZ418 and OZ277 activity in SARS-CoV2-infected Calu-3 cells revealed similar EC (5.3 μM and 11.6 μM, respectively), higher than the EC of remdesivir (1.0 ± 0.1 μM), but the SI of OZ418 was higher than OZ277. A third ozonide, OZ439, inhibited SARS-CoV-2 efficiently in Vero cells, but compared to OZ418 in Calu-3 cells, it showed higher toxicity. Improved inhibition of SARS-CoV-2 was observed when OZ418 was used together with remdesivir. Although the EC of ozonides might be clinically achieved in plasma after intravenous administration, sustained virus suppression in tissues will require further considerations, including drug combination. Our work supports the potential repurposing of ozonides and calls for future models.
随着严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）大流行的持续，人们正在努力寻找新的药物，并重新利用安全药物来治疗它。抗疟过氧化物具有抗病毒和抗癌活性。在这里，我们评估了青蒿琥酯（AS）和两种臭氧（OZ418 和 OZ277）对几种细胞系中的人α冠状病毒 NL63 和β冠状病毒 OC43 和 SARS-CoV-2 的活性。OZ418 在 NL63 感染的 Vero 细胞和 MK2 细胞中具有最佳的选择性指数（SI）。测试化合物的总体 SI 依赖于细胞类型。在 OC43 感染的人包皮成纤维细胞中，AS 的细胞相关 SI 最佳，≥17 μM，而 OZ418 和 OZ277 的 SI 分别为≥12 μM 和≥7 μM。AS 既不能抑制 Vero 细胞也不能抑制 Calu-3 细胞中的 SARS-CoV-2。OZ418 和 OZ277 在 SARS-CoV2 感染的 Calu-3 细胞中的活性比较表明，EC 相似（分别为 5.3 μM 和 11.6 μM），高于瑞德西韦（1.0 ± 0.1 μM）的 EC，但 OZ418 的 SI 高于 OZ277。第三种臭氧 OZ439 能有效抑制 Vero 细胞中的 SARS-CoV-2，但与 Calu-3 细胞中的 OZ418 相比，其毒性更高。当 OZ418 与瑞德西韦联合使用时，观察到对 SARS-CoV-2 的抑制作用增强。尽管臭氧在静脉给药后血浆中的 EC 可能在临床上达到，但需要进一步考虑包括药物联合使用在内的持续抑制病毒在组织中的扩散。我们的工作支持臭氧的潜在再利用，并呼吁未来的模型。
