Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 13, Pages 7333-7343Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202016208
Keywords
activity-based probes; cell-penetrating peptides; fluorescence; small ubiquitin like modifier (SUMO); ubiquitin
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Funding
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [831783]
- Gutwirth fellowship
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The fusion of modified cell-penetrating peptides with synthetic protein analogues can enhance the uptake efficiency of fluorescently labelled proteins in live cells, offering potential for functional studies.
Live-cell delivery of a fully synthetic protein having selectivity towards a particular target is a promising approach with potential applications for basic research and therapeutics. Cell-penetrating peptides (CPPs) allow the cellular delivery of proteins but mostly result in endosomal entrapment, leading to lack of bioavailability. Herein, we report the design and synthesis of a CPP fused to 4-((4-(dimethylamino)phenyl)azo)benzoic acid (DABCYL) to enhance cellular uptake of fluorescently labelled synthetic protein analogues in low micromolar concentration. The attachment of cyclic deca-arginine (cR10) modified with a single lysine linked to DABCYL to synthetic ubiquitin (Ub) and small ubiquitin-like modifier-2 (SUMO-2) scaffolds resulted in a threefold higher uptake efficacy in live cells compared to the unmodified cR10. We could also achieve cR10DABCYL-assisted delivery of Ub and a Ub variant (Ubv) based activity-based probes for functional studies of deubiquitinases in live cells.
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