Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
Viruses. 2022 May 24;14(6):1123. doi: 10.3390/v14061123.
Chikungunya virus (CHIKV) is a re-emerging arbovirus in the alphavirus genus. Upon infection, it can cause severe joint pain that can last years in some patients, significantly affecting their quality of life. Currently, there are no vaccines or anti-viral therapies available against CHIKV. Its spread to the Americas from the eastern continents has substantially increased the count of the infected by millions. Thus, there is an urgent need to identify therapeutic targets for CHIKV treatment. A potential point of intervention is the sphingosine-1-phosphate (S1P) pathway. Conversion of sphingosine to S1P is catalyzed by Sphingosine kinases (SKs), which we previously showed to be crucial pro-viral host factor during CHIKV infection. In this study, we screened inhibitors of SKs and identified a novel potent inhibitor of CHIKV infection-SLL3071511. We showed that the pre-treatment of cells with SLL3071511 in vitro effectively inhibited CHIKV infection with an EC value of 2.91 µM under both prophylactic and therapeutic modes, significantly decreasing the viral gene expression and release of viral particles. Our studies suggest that targeting SKs is a viable approach for controlling CHIKV replication.
基孔肯雅热病毒（CHIKV）是一种在甲病毒属中重新出现的虫媒病毒。感染后，它会导致一些患者持续数年的严重关节疼痛，严重影响他们的生活质量。目前，尚无针对 CHIKV 的疫苗或抗病毒疗法。它从东部大陆传播到美洲，使感染人数增加了数百万。因此，迫切需要确定 CHIKV 治疗的治疗靶点。一个潜在的干预点是鞘氨醇-1-磷酸（S1P）途径。我们之前的研究表明，丝氨酸激酶（SKs）是 CHIKV 感染过程中关键的促病毒宿主因子，它可以催化鞘氨醇转化为 S1P。在这项研究中，我们筛选了 SKs 的抑制剂，并发现了一种新型有效的 CHIKV 感染抑制剂-SLL3071511。我们表明，在体外，用 SLL3071511 预处理细胞可有效抑制 CHIKV 感染，在预防和治疗两种模式下，EC 值均为 2.91µM，显著降低了病毒基因表达和病毒颗粒释放。我们的研究表明，靶向 SKs 是控制 CHIKV 复制的一种可行方法。
