Discovery of next-generation dengue NS4B inhibitors

项目5--摘要 该项目的目标是发现下一代登革热NS4B抑制剂。我们目前有一起泛登革热 血清型NS4B抑制剂NITD-688正在进行I期临床试验。临床前研究结果表明有两种潜在的风险 可能会威胁到这种化合物的进一步发展。因此，我们将开发一种第二代化合物来 减轻债务。我们将通过追求三个目标来实现这一目标。(一)优化下一代登革热 NS4B抑制剂。我们制定了全面的药物化学优化策略，以提高 复合属性。(Ii)进行临床前鉴定并提供可供IND使用的下一代NS4B 抑制剂。(3)测定NITD-688的作用模式和抗性电位。NS4B是一种跨膜蛋白 通过与其他病毒和宿主蛋白相互作用而参与复制复合体的蛋白质。我们会带上 用化学蛋白质组学、生化和细胞学的方法来确定化合物抑制的机制。是这样的 这些知识可以应用于其他膜蛋白，用于抗病毒的发现。

PROJECT 5 – ABSTRACT The goal of this project is to discover next-generation dengue NS4B inhibitors. We currently have a pan-dengue serotype NS4B inhibitor NITD-688 in phase I clinical trial. Preclinical results suggest two potential liabilities that might threaten this compound for further development. Thus, we will develop a second-generation compound to mitigate the liabilities. We will achieve the goal by pursuing three aims. (i) Optimize the next generation of dengue NS4B inhibitor. We have developed a comprehensive medicinal chemistry optimization strategy to improve the compound properties. (ii) Conduct preclinical characterization and deliver an IND-ready next-generation NS4B inhibitor. (iii) Determine the mode-of-action and resistance potential of NITD-688. NS4B is a transmembrane protein that participates in replication complex through interacting with other viral and host proteins. We will take chemo-proteomic, biochemical, and cellular approaches to define the mechanism of compound inhibition. Such knowledge can be applied to other membrane proteins for antiviral discovery.