Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor

被引:96
作者
Abegg, Daniel [1 ]
Gasparini, Giulio [1 ,2 ]
Hoch, Dominic G. [1 ]
Shuster, Anton [1 ]
Bartolami, Eline [1 ]
Matile, Stefan [1 ]
Adibekian, Alexander [1 ]
机构
[1] Univ Geneva, Sch Chem & Biochem, Natl Ctr Competence Res NCCR Chem Biol, CH-1211 Geneva, Switzerland
[2] Firmenich Co, Div Res & Dev, CH-1211 Geneva, Switzerland
关键词
UNFOLDED PROTEIN RESPONSE; DRUG-DELIVERY SYSTEMS; PENETRATING-PEPTIDES; SIRNA DELIVERY; BH3-ONLY PROTEINS; INDUCE APOPTOSIS; POLY(DISULFIDE)S; CELLS; BAK; DNA;
D O I
10.1021/jacs.6b09643
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications.
引用
收藏
页码:231 / 238
页数:8
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