Enhanced Live-Cell Delivery of Synthetic Proteins Assisted by Cell-Penetrating Peptides Fused to DABCYL

Shaswati Mandal, Guy Mann, Gandhesiri Satish, Ashraf Brik

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)7333-7343
Number of pages11
JournalAngewandte Chemie - International Edition
Volume60
Issue number13
DOIs
StatePublished - 22 Mar 2021
Externally publishedYes

Keywords

  • activity-based probes
  • cell-penetrating peptides
  • fluorescence
  • small ubiquitin like modifier (SUMO)
  • ubiquitin

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)

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