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  • Title: Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism.
    Author: Liu HY, Li Z, Reindl T, He Z, Qiu X, Golden RP, Donovan KA, Bailey A, Fischer ES, Zhang T, Gray NS, Yang PL.
    Journal: Nat Commun; 2024 Jun 19; 15(1):5179. PubMed ID: 38898037.
    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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