2. Academic Validation
  3. Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism

Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism

  • Nat Commun. 2024 Jun 19;15(1):5179. doi: 10.1038/s41467-024-49161-9.
Han-Yuan Liu # 1,  Zhengnian Li # 2,  Theresia Reindl 1,  Zhixiang He 3,  Xueer Qiu 4,  Ryan P Golden 2,  Katherine A Donovan 3 5,  Adam Bailey 4,  Eric S Fischer 3 5,  Tinghu Zhang 2,  Nathanael S Gray 6,  Priscilla L Yang 7
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Pathology & Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. nsgray01@stanford.edu.
  • 7 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. ply@stanford.edu.
  • # Contributed equally.
PMID: 38898037 DOI: 10.1038/s41467-024-49161-9
Abstract

Viral genetic diversity presents significant challenges in developing antivirals with broad-spectrum activity and high barriers to resistance. Here we report development of proteolysis targeting chimeras (PROTACs) targeting the Dengue virus envelope (E) protein through coupling of known E fusion inhibitors to ligands of the CRL4CRBN E3 ubiquitin Ligase. The resulting small molecules block viral entry through inhibition of E-mediated membrane fusion and interfere with viral particle production by depleting intracellular E in infected Huh 7.5 cells. This activity is retained in the presence of point mutations previously shown to confer partial resistance to the parental inhibitors due to decreased inhibitor-binding. The E PROTACs also exhibit broadened spectrum of activity compared to the parental E inhibitors against a panel of mosquito-borne flaviviruses. These findings encourage further exploration of targeted protein degradation as a differentiated and potentially advantageous modality for development of broad-spectrum direct-acting antivirals.

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