Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 9190400, Israel.
Viruses. 2022 Aug 11;14(8):1750. doi: 10.3390/v14081750.
Flavivirus infections, such as those caused by dengue and West Nile viruses, emerge as new challenges for the global healthcare sector. It has been found that these two viruses encode ion channels collectively termed viroporins. Therefore, drug molecules that block such ion-channel activity can serve as potential antiviral agents and may play a primary role in therapeutic purposes. We screened 2839 FDA-approved drugs and compounds in advanced experimental phases using three bacteria-based channel assays to identify such ion channel blockers. We primarily followed a negative genetic screen in which the channel is harmful to the bacteria due to excessive membrane permeabilization that can be relieved by a blocker. Subsequently, we cross-checked the outcome with a positive genetic screen and a pH-dependent assay. The following drugs exhibited potential blocker activities: plerixafor, streptomycin, tranexamic acid, CI-1040, glecaprevir, kasugamycin, and mesna were effective against dengue virus DP1. In contrast, idasanutlin, benzbromarone, 5-azacytidine, and plerixafor were effective against West Nile Virus MgM. These drugs can serve as future antiviral therapeutic agents following subsequent in vitro and in vivo efficacy studies.
黄病毒感染，如登革热和西尼罗河病毒引起的感染，对全球医疗保健领域构成新的挑战。研究发现，这两种病毒共同编码一种离子通道，称为病毒孔道蛋白。因此，能阻断这些离子通道活性的药物分子可能成为有潜力的抗病毒药物，并可能在治疗目的中发挥主要作用。我们使用三种基于细菌的通道测定法，对处于高级实验阶段的 2839 种 FDA 批准的药物和化合物进行了筛选，以确定这类离子通道阻滞剂。我们主要采用负遗传筛选，即由于膜过度渗透而对细菌有害的通道，可被阻滞剂缓解。随后，我们用正遗传筛选和 pH 依赖性测定法交叉检查结果。以下药物表现出潜在的阻滞剂活性：plerixafor、链霉素、氨甲环酸、CI-1040、glecaprevir、井冈霉素和美司钠对登革热病毒 DP1 有效。相比之下，idasanutlin、苯溴马隆、5-氮杂胞苷和plerixafor 对西尼罗河病毒 MgM 有效。这些药物在进行后续的体外和体内疗效研究后，可作为未来的抗病毒治疗药物。
