Disubstituted pyrimidine inhibitors of dengue virus entry

登革病毒（DENV）是当今影响人类的最重要的蚊媒病毒性疾病。据估计，每年有1亿人感染登革热病毒，导致登革热和登革出血热（DHF）。由于估计有25亿人生活在有流行病传播风险的地区，并且由于DENV感染的数量和导致DHF的感染比例在过去20年中都有所上升，因此抗DENV治疗剂或抗DENV疫苗的缺乏是日益增长的公共卫生问题。我们最近发现了两个独立的系列的抑制剂DV进入的基础上二取代嘧啶和α-酮氰腙支架，这两个似乎阻止病毒进入的融合步骤。在这里，我们建议利用集中的药物化学，生物化学和病毒学的组合来了解这些化合物的抗DENV活性的结构-活性关系以及它们的作用机制。

Dengue virus (DENV) is the most important mosquito-bome viral disease affecting humans today. An estimated 100 million people are infected with dengue virus annually, leading to dengue fever and dengue hemorrhagic fever (DHF). Since there are an estimated 2.5 billion people living in areas at risk for epidemic transmission and since both the number of DENV infections and the proportion of infections resulting in DHF have escalated in the past 20 years, the absence of anti-DENV therapeutics or an anti-DENV vaccine is a growing public health concern. We recently discovered two independent series of inhibitors of DV entry based on disubstituted pyrimidine and alpha-ketocyanohydrazone scaffolds, both of which appear to block the fusion step of virus entry. Here, we propose to utilize a combination of focused medicinal chemistry, biochemistry, and virology to understand the structure-activity relationships governing the anti-DENV activity of these compounds as well as their mechanism of action.