Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20892, USA.
Sci Rep. 2022 Apr 15;12(1):6294. doi: 10.1038/s41598-022-10293-x.
Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a heparan sulfate-spike complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar heparan sulfate-binding activities but with reduced affinity for DNA topoisomerases may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.
刺突介导的 SARS-CoV-2 进入人呼吸道上皮细胞是 COVID-19 的一个有吸引力的治疗靶点。除了蛋白质受体，SARS-CoV-2 的刺突（S）蛋白还与肝素硫酸酯结合，肝素硫酸酯是一种带负电荷的糖胺聚糖（GAG），附着在细胞表面的某些膜蛋白上。这种相互作用促进了刺突与下游受体的结合，从而促进病毒进入。在这里，我们表明米托蒽醌，一种 FDA 批准的拓扑异构酶抑制剂，靶向肝素硫酸酯-刺突复合物，损害刺突在病毒进入中的融合功能。作为单一药物，米托蒽醌抑制基于细胞的模型中和人肺 EpiAirway 3D 组织中真实 SARS-CoV-2 株的感染。基因表达谱支持质膜是米托蒽醌的主要靶点，但也强调了一种针对核小体动力学的不良活性。我们提出，具有类似肝素硫酸酯结合活性但与 DNA 拓扑异构酶亲和力降低的米托蒽醌类似物可能提供一种替代疗法，以克服疫苗接种后时代的突破性感染。
