August 1, 2019
384-well plates with 50 ÎźL FluoroBrite DMEM media (Thermo Fisher Scientific A18967) containing 10% FBS per well a day before compound treatment. Compounds and 100 nM dBET6 were dispensed using a D300e Digital Dispenser (HP), normalized to 0.5% DMSO, and incubated with cells for 5 h. The assay plate was imaged immediately using an Acumen High Content Imager (TTP Labtech) with 488 nm and 56;384-well plates with 50 ÎźL FluoroBrite DMEM media (Thermo Fisher Scientific A18967) containing 10% FBS per well a day before compound treatment. Compounds and 100 nM dBET6 were dispensed using a D300e Digital Dispenser (HP), normalized to 0.5% DMSO, and incubated with cells for 5 h. The assay plate was imaged immediately using an Acumen High Content Imager (TTP Labtech) with 488 nm and 56
Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.
de Wispelaere, M; Du, G; Donovan, KA; Zhang, T; Eleuteri, NA; Yuan, JC; Kalabathula, J; Nowak, RP; Fischer, ES; Gray, NS; Yang, PL;
Journal: Nat Commun Pages: 3468