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Biological Chemistry

Two new ways to get proteins into cells

Disrupting endosomes and skipping endosomes entirely ease cell entry

by Stu Borman
July 24, 2017 | A version of this story appeared in Volume 95, Issue 30

Schematic shows that nanobody conjugated with cell-penetrating peptide can directly enter the cell cytosol, and nanobody-antigen recognition can occur internally.
Credit: Henry D. Herce/Technical U Darmstadt
A nanobody-peptide pair directly enters the cell cytosol, where the nanobody can bind its antigen.

Proteins can be important therapeutics, but in many cases their potential is limited because their polarity and large size prevent them from traversing cell membranes and entering cells, where their molecular targets may be located. Cell-penetrating peptides can shepherd proteins into cells, but in many cases the proteins are taken up by and retained in cell endosomes and thus still don’t reach the cytosol, the aqueous component of the cytoplasm. Two groups have now devised novel methods for getting proteins into the cytosol. Shiroh Futaki of Kyoto University and coworkers treat cells with an antibody and a peptide derivatized with an acidic group (Nat. Chem. 2017, DOI: 10.1038/nchem.2779). The pair enter an endosome, but the peptide disrupts the endosome’s negatively charged membrane, releasing the antibody. And Henry D. Herce and M. Cristina Cardoso of the Technical University of Darmstadt, Dominik Schumacher and Christian P. R. Hackenberger of Leibniz Institute for Molecular Pharmacology and Humboldt University of Berlin, and coworkers report a different strategy. They get a nanobody (antibody fragment) and nanobody-antigen conjugates into the cytosol or nucleus by using a technique called expressed protein ligation to link them to endosome-avoiding cyclic cell-penetrating peptides (Nat. Chem. 2017, DOI: 10.1038/nchem.2811). The techniques could ease the use of antibodies to target proteins in living cells.


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