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Biomacromolecules. 2019 May 13;20(5):1849-1859. doi: 10.1021/acs.biomac.8b01299. Epub 2019 Apr 1.

Oligoarginine-Bearing Tandem Repeat Penetration-Accelerating Sequence Delivers Protein to Cytosol via Caveolae-Mediated Endocytosis.

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Department of Medical Technology, Graduate School of Health Sciences , Niigata University , 746 Asahimachidori-2 , Chuo-ku, Niigata , Niigata 951-8518 , Japan.
Institute for Chemical Research , Kyoto University , Uji , Kyoto 611-0011 , Japan.
Graduate School of Science , Osaka Prefecture University , Naka-ku, Sakai , Osaka 599-8570 , Japan.
Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy , Osaka Ohtani University , Tondabayashi , Osaka 584-8540 , Japan.


To facilitate the cytosolic delivery of larger molecules such as proteins, we developed a new cell-penetrating peptide sequence, named Pas2r12, consisting of a repeated Pas sequence (FFLIG-FFLIG) and d-dodeca-arginine (r12). This peptide significantly enhanced the cellular uptake and cytosolic release of enhanced green fluorescent protein and immunoglobulin G as cargos. We found that simply mixing Pas2r12 with cargos could generate cytosolic introducible forms. The cytosolic delivery of cargos by Pas2r12 was found to be an energy-requiring process, to rely on actin polymerization, and to be suppressed by caveolae-mediated endocytosis inhibitors (genistein and methyl-β-cyclodextrin) and small interfering RNA against caveolin-1. These results suggest that Pas2r12 enhances membrane penetration of cargos without the need for cross-linking and that caveolae-mediated endocytosis may be the route by which cytosolic delivery is enhanced.


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