PDF(Pubmed)
Abstract：
Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.
摘要：
靶向蛋白质降解已被广泛采用作为消除已建立和先前顽固的治疗靶标的新方法。在这里，我们报告了登革热病毒包膜（E）蛋白的小分子降解物的开发。我们开发了两类二价E降解剂，连接两个先前报道的E结合小分子，GNF-2和CVM-2-12-2，用于基于戊二酰亚胺的CRL4CRBN连接酶招募者，以实现蛋白体介导的E蛋白降解。ZXH-2-107(基于GNF-2)是具有ABL抑制的E降解剂,而ZXH-8-004(基于CVM-2-12-2)是选择性和有效的E降解剂。这两种化合物提供了概念证明，即使用二价降解剂可以有效消除诸如病毒包膜蛋白之类的难药用靶标，并为未来开发新一类抗病毒药物提供了起点。
