Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medicine, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94305, USA.
Department of Microbiology and Immunology, Stanford University School of Medicine, 279 Campus Drive, Palo Alto, CA, 94305, USA.
Adv Sci (Weinh). 2024 Oct;11(40):e2405829. doi: 10.1002/advs.202405829. Epub 2024 Aug 15.
Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4 ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E-degrader with ABL inhibitory activity 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 of direct-acting antiviral drugs.
靶向蛋白降解已被广泛应用于消除已确立和以前难以治疗的治疗靶点的新方法。在这里，据报道开发了登革热病毒包膜 (E) 蛋白的小分子降解剂。通过将两种先前报道的 E 结合小分子 GNF-2 和 CVM-2-12-2 连接到基于戊二酰亚胺的 CRL4 连接酶招募物上，开发了两类二价 E 降解剂，以实现 E 蛋白的蛋白酶体介导降解。ZXH-2-107（基于 GNF-2）是一种具有 ABL 抑制活性的 E 降解剂，而 ZXH-8-004（基于 CVM-2-12-2）是一种选择性和有效的 E 降解剂。这两种化合物提供了一个概念证明，即即使是像病毒包膜蛋白这样难以成药的靶点，也可以使用二价降解剂有效地消除，为未来开发一类新型直接作用抗病毒药物提供了起点。
