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Cytosolic Delivery of Macromolecules in Live Human Cells Using the Combined Endosomal Escape Activities of a Small Molecule and Cell Penetrating Peptides.

Abstract：

:Ineffective cellular delivery is a common problem in numerous biological applications. Developing delivery reagents that work robustly in a variety of experimental settings remains a challenge. Herein, we report how peptides derived from the prototypical cell penetrating peptide TAT can be used in combination with a small molecule, UNC7938, to deliver macromolecules into the cytosol of cells by a simple co-incubation protocol. We establish successful delivery of peptides, DNA plasmids, and a single-chain variable fragment antibody. We also demonstrate that delivery works in hard-to-transfect mammalian cells and under conditions typically inhibitory to cell-penetrating peptides. Mechanistically, UNC7938 destabilizes the membrane of endosomes. This, in turn, enhances the endosome-leakage activity of cell-penetrating peptides and facilitates the endosomal escape of macromolecules initially internalized by mammalian cells via endocytosis. This combined selective membrane-destabilization represents a new chemical space for delivery tools and provides a novel solution to the problem of endosomal entrapment that often limits the effectiveness of reagent-based delivery approaches.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Allen J,Najjar K,Erazo-Oliveras A,Kondow-McConaghy HM,Brock DJ,Graham K,Hager EC,Marschall ALJ,Dübel S,Juliano RL,Pellois JP

doi

10.1021/acschembio.9b00585

subject

Has Abstract

pub_date

2019-12-20 00:00:00

pages

2641-2651

issue

12

eissn

1554-8929

issn

1554-8937

journal_volume

14

pub_type

杂志文章

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