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Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2018-02-06 00:00:00 , DOI: 10.1021/acsinfecdis.7b00236
Pedro O. Miranda , Beatrice Cubitt , Nicholas T. Jacob , Kim D. Janda , Juan C. de la Torre

Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus–host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-4′-methoxy-[1,1′-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus–host interactions, as well as lead candidate structures to develop antiarenaviral drugs.

中文翻译:

挖掘Kröhnke吡啶文库的抗Arenavirus活性

几种芳烃病毒会导致人类出血热(HF)疾病,并在其流行地区代表重要的公共卫生问题。此外,有证据表明,全世界分布的原型芳烃病毒淋巴细胞性脉络膜脑膜炎病毒是一种具有临床意义的被忽视的人类病原体。目前尚无获得许可的沙粒病毒疫苗,目前的抗沙粒病毒治疗仅限于非局部使用利巴韦林,但仅部分有效。因此,迫切需要一种新型的抗人类病原体病毒的治疗方法,这一任务将通过鉴定具有抗阿拉伯病毒活性的化合物而得以简化,这些化合物可以用作探针,以鉴定适合于靶向的沙粒病毒-宿主相互作用以及先导化合物开发未来的抗ARENA病毒药物。b ] [1,4]二恶英-6-基)-4'-甲氧基-[1,1'-联苯] -3-基)噻吩-2-羧酰胺]具有较强的抗淋巴细胞性脉络膜脑膜炎病毒(LCMV)活性在培养的细胞中。KP-146不会抑制LCMV细胞进入,但会干扰负责指导病毒RNA复制和基因转录的LCMV核糖核蛋白(vRNP)的活性,以及​​由LCMV基质Z蛋白介导的出芽过程。在KP-146存在下连续传代后,对KP-146抗性增强的LCMV变体没有出现。我们的发现支持考虑使用Kröhnke吡啶支架作为鉴定化合物的有价值的来源,这些化合物可作为剖析沙粒病毒与宿主相互作用的工具,以及开发抗ARENA病毒药物的主要候选结构。
更新日期:2018-02-06
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