Singh Anamika, Arkin Isaiah T
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 9190400, Israel.
Pharmaceuticals (Basel). 2022 Mar 24;15(4):396. doi: 10.3390/ph15040396.
SARS-CoV-2 is the etiological agent COVID-19, one of the most impactful health crises afflicting humanity in recent decades. While research advances have yielded several treatment and prevention options, the pandemic is slow to abate, necessitating an expansion of our treatment arsenal. As a member of the coronaviridae, SARS-CoV-2 contains several ion channels, of which E and 3a are the best characterized. Since ion channels as a family are excellent drug targets, we sought to inhibit both viroporins as a means to curb infectivity. In a previous targeted study, we identified several blockers to each channel from an extensive drug repurposing library. Herein, we examined the ability of said compounds on the whole virus in cellulo. Gratifyingly, many of the blockers exhibited antiviral activity in a stringent assay examining protection from viral-driven death. In particular, darapladib and flumatinib, both 3a blockers, displayed potent antiviral activity. Furthermore, appreciable synergism between flumatinib and several E blockers was identified in a concentration regime in which the compounds are present in human plasma following oral administration. Taken together, targeting ion channels represents a promising approach to both augment and complement our antiviral arsenal against COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是冠状病毒病19（COVID-19）的病原体，是近几十年来困扰人类的最具影响力的健康危机之一。尽管研究进展已经产生了几种治疗和预防方案，但疫情缓解缓慢，因此有必要扩充我们的治疗手段。作为冠状病毒科的一员，SARS-CoV-2包含多个离子通道，其中E通道和3a通道的特征最为明确。由于离子通道作为一个家族是极佳的药物靶点，我们试图抑制这两种病毒孔蛋白，以此作为抑制传染性的一种手段。在之前的一项靶向研究中，我们从一个广泛的药物重新利用文库中为每个通道鉴定了几种阻滞剂。在此，我们在细胞内研究了上述化合物对完整病毒的作用。令人欣慰的是，在一项严格的检测病毒驱动死亡防护能力的试验中，许多阻滞剂都表现出了抗病毒活性。特别是，同为3a通道阻滞剂的达拉匹林和氟马替尼表现出了强大的抗病毒活性。此外，在口服给药后化合物存在于人体血浆中的浓度范围内，发现氟马替尼与几种E通道阻滞剂之间存在明显的协同作用。综上所述，靶向离子通道是一种有前景的方法，可用于扩充和补充我们对抗COVID-19的抗病毒手段。
