Discovery of Potent Degraders of the Dengue Virus Envelope Protein

Zhengnian Li; Han‐Yuan Liu; Zhixiang He; Antara Chakravarty; Ryan P. Golden; Zixuan Jiang; Inchul You; Hong Yue; Katherine A. Donovan; Guangyan Du; Jianwei Che; Jason Tse; Isaac Che; Wenchao Lu; Eric S. Fischer; Tinghu Zhang; Nathanael S. Gray; Priscilla L. Yang

doi:10.1002/advs.202405829

BiochemistryAdvanced ScienceAug 15, 2024

Peer-reviewed journal article

Discovery of Potent Degraders of the Dengue Virus Envelope Protein

Zhengnian Li iD, Han‐Yuan Liu iD, Zhixiang He iD, Antara Chakravarty iD, Ryan P. Golden iD, Zixuan Jiang iD, Inchul You, Hong Yue iD, Katherine A. Donovan iD, Guangyan Du, Jianwei Che iD, Jason Tse iD, Isaac Che, Wenchao Lu iD, Eric S. Fischer iD, Tinghu Zhang iD, Nathanael S. Gray iD, Priscilla L. Yang iD

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.

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