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Discovery of Potent Degraders of the Dengue Virus Envelope Protein.
Li, Zhengnian; Liu, Han-Yuan; He, Zhixiang; Chakravarty, Antara; Golden, Ryan P; Jiang, Zixuan; You, Inchul; Yue, Hong; Donovan, Katherine A; Du, Guangyan; Che, Jianwei; Tse, Jason; Che, Isaac; Lu, Wenchao; Fischer, Eric S; Zhang, Tinghu; Gray, Nathanael S; Yang, Priscilla L.
Afiliación
  • Li Z; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Liu HY; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA.
  • He Z; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Chakravarty A; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA.
  • Golden RP; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Jiang Z; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • You I; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Yue H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Donovan KA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • Du G; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Che J; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • Tse J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Che I; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • Lu W; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Fischer ES; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Zhang T; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Yang PL; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
bioRxiv ; 2024 Jun 02.
Article en En | MEDLINE | ID: mdl-38854003
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos