Sharma Rajesh, Fatma Benazir, Saha Amrita, Bajpai Sailesh, Sistla Srinivas, Dash Paban Kumar, Parida Manmohan, Kumar Pravindra, Tomar Shailly
Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India.
Division of Virology, Defence Research and Development Establishment, Gwalior 474002, India.
Virology. 2016 Nov;498:265-276. doi: 10.1016/j.virol.2016.08.029. Epub 2016 Sep 9.
The protein-protein interactions (PPIs) of the transmembrane glycoprotein E2 with the hydrophobic pocket on the surface of capsid protein (CP) plays a critical role in alphavirus life cycle. Dioxane based derivatives targeting PPIs have been reported to possess antiviral activity against Sindbis Virus (SINV), the prototype alphavirus. In this study, the binding of picolinic acid (PCA) to the conserved hydrophobic pocket of capsid protein was analyzed by molecular docking, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR) and fluorescence spectroscopy. The binding constant KD obtained for PCA was 2.1×10(-7)M. Additionally, PCA significantly inhibited CHIKV replication in infected Vero cells, decreasing viral mRNA and viral load as assessed by qRT-PCR and plaque reduction assay, respectively. This study is suggestive of the potential of pyridine ring compounds as antivirals against alphaviruses and may serve as the basis for the development of PCA based drugs against alphaviral diseases.
跨膜糖蛋白E2与衣壳蛋白（CP）表面疏水口袋之间的蛋白质-蛋白质相互作用（PPI）在甲病毒生命周期中起着关键作用。据报道，靶向PPI的基于二恶烷的衍生物对甲型病毒原型辛德毕斯病毒（SINV）具有抗病毒活性。在本研究中，通过分子对接、等温滴定量热法（ITC）、表面等离子体共振（SPR）和荧光光谱法分析了吡啶甲酸（PCA）与衣壳蛋白保守疏水口袋的结合。PCA的结合常数KD为2.1×1０⁻⁷M。此外，PCA显著抑制感染的Vero细胞中的基孔肯雅病毒（CHIKV）复制，分别通过qRT-PCR和噬斑减少试验评估，降低了病毒mRNA和病毒载量。本研究表明吡啶环化合物作为抗甲病毒药物具有潜力，并可能为开发基于PCA的抗甲病毒疾病药物奠定基础。
