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

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 CRL4^CRBN 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 compare

SUBMITTER: Liu HY 

PROVIDER: S-EPMC11187112 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature