Discovery of Potent Degraders of the Dengue Virus Envelope Protein

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<sup>CRBN</sup> 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.

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Publication Details

Journal
Advanced Science
Published
2024-08-15
DOI
https://doi.org/10.1002/advs.202405829
Citations
9
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
4.89

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article

Discovery of Potent Degraders of the Dengue Virus Envelope Protein

Zixuan Jiang, Antara Chakravarty, Wenchao Lu, Eric S. Fischer et al.
9 citations
Advanced Science
Mosquito-borne diseases and control
4.89
article

Discovery of Potent Degraders of the Dengue Virus Envelope Protein

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

Abstract

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<sup>CRBN</sup> 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.

Advanced ScienceVol. 11(40)
Harvard University (US), Dana-Farber Cancer Institute (US), Stanford Medicine (US), Stanford University (US)
Mark Foundation For Cancer Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 5%
Mosquito-borne diseases and control
4.89
DOIOpen Access PDFOpenAlex
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