Howe Matthew K, Speer Brittany L, Hughes Philip F, Loiselle David R, Vasudevan Subhash, Haystead Timothy A J
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Emerging Infectious Diseases Program, Duke-NUS Graduate and Medical School, Singapore.
Antiviral Res. 2016 Jun;130:81-92. doi: 10.1016/j.antiviral.2016.03.017. Epub 2016 Apr 4.
An estimated three billion people are at risk of Dengue virus (DENV) infection worldwide and there are currently no approved therapeutic interventions for DENV infection. Due to the relatively small size of the DENV genome, DENV is reliant on host factors throughout the viral life cycle. The inducible form of Heat Shock Protein 70 (Hsp70i) has been implicated as a host factor in DENV pathogenesis, however the complete role remains to be elucidated. Here we further illustrate the importance of Hsp70i in dengue virus pathogenesis and describe the antiviral activity of the allosteric small molecule inhibitor that is selective for Hsp70i, called HS-72. In monocytes, Hsp70i is expressed at low levels preceding DENV infection, but Hsp70i expression is induced upon DENV infection. Targeting Hsp70i with HS-72, results in a dose dependent reduction in DENV infected monocytes, while cell viability was maintained. HS-72 works to reduce DENV infection by inhibiting the entry stage of the viral life cycle, through disrupting the association of Hsp70i with the DENV receptor complex. This work highlights Hsp70i as an antiviral target and HS-72 as a potential anti-DENV therapeutic agent.
据估计，全球有30亿人面临感染登革病毒（DENV）的风险，目前尚无针对DENV感染的获批治疗干预措施。由于DENV基因组相对较小，DENV在整个病毒生命周期中都依赖宿主因子。热休克蛋白70的可诱导形式（Hsp70i）被认为是DENV发病机制中的一种宿主因子，但其完整作用仍有待阐明。在此，我们进一步阐述了Hsp70i在登革病毒发病机制中的重要性，并描述了对Hsp70i具有选择性的变构小分子抑制剂HS-72的抗病毒活性。在单核细胞中，Hsp70i在DENV感染前表达水平较低，但DENV感染后Hsp70i表达会被诱导。用HS-72靶向Hsp70i，会导致DENV感染的单核细胞呈剂量依赖性减少，同时细胞活力得以维持。HS-72通过破坏Hsp70i与DENV受体复合物的结合，抑制病毒生命周期的进入阶段，从而减少DENV感染。这项工作突出了Hsp70i作为抗病毒靶点以及HS-72作为潜在抗DENV治疗剂的作用。
