Angewandte Chemie International Edition · 2021 · 68 citations · 31 references
PharmacyMolecular PharmaceuticsPharmaceuticsDrug DeliveryDrug DesignProtein EngineeringCell-penetrating Delivery SystemsCell-penetrating PeptidesPeptide DeliveryProtein DeliveryProtein TargetingTherapeutic Protein EngineeringArginine-rich PeptidesCellular Uptake ModulationEndosomal RetentionEntrapmentPeptide Delivery SystemsPeptide-based Drug CarriersPeptide-mediated DeliverySynthetic Analogues
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.
31
A Comprehensive Model for the Cellular Uptake of Cationic Cell‐penetrating Peptides
Falk Duchardt, Mariola Fotin‐Mleczek, Heinz Schwarz et al. · Traffic · 2007 · 764 citations
Gisela Lättig-Tünnemann, Manuel Prinz, Daniel Hoffmann et al. · Nature Communications · 2011 · 304 citations · Full text
A Strategy for Modulation of Enzymes in the Ubiquitin System
Andreas Ernst, G.V. Avvakumov, Jiefei Tong et al. · Science · 2013 · 297 citations · Full text