Yatawara Achani, Gaidos Gabriel, Rupasinghe Chamila N, O'Hara Bethany A, Pellegrini Maria, Atwood Walter J, Mierke Dale F
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA.
J Pept Sci. 2015 Mar;21(3):236-42. doi: 10.1002/psc.2731. Epub 2014 Dec 19.
The JC polyomavirus (JCPyV) infects approximately 50% of the human population. In healthy individuals, the infection remains dormant and asymptomatic, but in immuno-suppressed patients, it can cause progressive multifocal leukoencephalopathy (PML), a potentially fatal demyelinating disease. Currently, there are no drugs against JCPyV infection nor for the treatment of PML. Here, we report the development of small-molecule inhibitors of JCPyV that target the initial interaction between the virus and host cell and thereby block viral entry. Utilizing a combination of computational and NMR-based screening techniques, we target the LSTc tetrasaccharide binding site within the VP1 pentameric coat protein of JCPyV. Four of the compounds from the screen effectively block viral infection in our in vitro assays using SVG-A cells. For the most potent compound, we used saturation transfer difference NMR to determine the mode of binding to purified pentamers of JCPyV VP1. Collectively, these results demonstrate the viability of this class of compounds for eventual development of JCPyV-antiviral therapeutics.
JC多瘤病毒（JCPyV）感染了大约50%的人类。在健康个体中，感染处于潜伏状态且无症状，但在免疫抑制患者中，它可引发进行性多灶性白质脑病（PML），这是一种潜在致命的脱髓鞘疾病。目前，尚无针对JCPyV感染的药物，也没有治疗PML的药物。在此，我们报告了JCPyV小分子抑制剂的研发情况，这些抑制剂靶向病毒与宿主细胞之间的初始相互作用，从而阻断病毒进入。利用基于计算和核磁共振的筛选技术相结合的方法，我们靶向JCPyV VP1五聚体外壳蛋白内的LSTc四糖结合位点。在使用SVG - A细胞的体外试验中，筛选出的四种化合物有效地阻断了病毒感染。对于最有效的化合物，我们使用饱和转移差异核磁共振来确定其与纯化的JCPyV VP1五聚体的结合模式。总体而言，这些结果证明了这类化合物最终用于开发JCPyV抗病毒疗法的可行性。
