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NS 4 B抑制剂。我们目前有一个泛登革热 血清型NS 4 B抑制剂NITD-688在I期临床试验中。临床前结果表明， 可能会威胁到这个化合物的进一步发展因此，我们将开发第二代化合物， 减轻责任。我们将通过追求三个目标来实现这一目标。(i)优化下一代登革热 NS 4 B抑制剂。我们已经开发了一种全面的药物化学优化策略，以提高 复合特性(ii)进行临床前表征并交付IND就绪的下一代NS 4 B 抑制剂. (iii)确定NITD-688的作用方式和电阻电位。NS 4 B是一种跨膜 通过与其它病毒和宿主蛋白质相互作用而参与复制复合体的蛋白质。我们将采取 化学蛋白质组学、生物化学和细胞方法来确定化合物抑制的机制。等 这些知识可以应用于其他膜蛋白以发现抗病毒药物。

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.