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

Han-Yuan Liu, Zhengnian Li, Theresia Reindl, Zhixiang He, Xueer Qiu, Ryan P. Golden, Katherine A. Donovan, Adam Bailey, Eric S. Fischer, Tinghu Zhang, Nathanael S. Gray () and Priscilla L. Yang ()
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Han-Yuan Liu: Stanford University School of Medicine
Zhengnian Li: Stanford University School of Medicine
Theresia Reindl: Stanford University School of Medicine
Zhixiang He: Dana-Farber Cancer Institute
Xueer Qiu: University of Wisconsin–Madison
Ryan P. Golden: Stanford University School of Medicine
Katherine A. Donovan: Dana-Farber Cancer Institute
Adam Bailey: University of Wisconsin–Madison
Eric S. Fischer: Dana-Farber Cancer Institute
Tinghu Zhang: Stanford University School of Medicine
Nathanael S. Gray: Stanford University School of Medicine
Priscilla L. Yang: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49161-9

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