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
  • 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. [email protected].
  • 7. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • # 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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