Journal
MOLECULAR PHARMACEUTICS
Volume 12, Issue 8, Pages 2962-2971Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00233
Keywords
intracellular protein delivery; toxin translocation; diphtheria toxin
Funding
- Canadian Institutes of Health Research (CIHR)
- National Science and Engineering Research Council of Canada [RGPIN 4184057]
- Brain Canada Multi-Investigator Research Initiative Grant
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Platforms enabling targeted delivery of proteins into cells are needed to fully realize the potential of protein-based therapeutics with intracellular sites-of-action. Bacterial toxins are attractive systems to consider as templates for designing protein transduction systems as they naturally bind and enter specific cells with high efficiency. Here we investigated the capacity of diphtheria toxin to function as an intracellular protein delivery vector. We report that diphtheria toxin delivers an impressive array of passenger proteins spanning a range of sizes, structures, and stabilities into cells in a manner that indicates that they are invisible to the translocation machinery. Further, we show that a-amylase delivered into cells by a detoxified diphtheria toxin chimera digests intracellular glycogen in live cells, providing evidence that delivered cargo is folded, active, and abundant. The efficiency and versatility of diphtheria toxin over existing systems open numerous possibilities for intracellular delivery of bioactive proteins.
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