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Issue 10, 2020
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Intracellular delivery of a peptide nucleic acid-based hybrid of an autophagy inducing peptide with a cell-penetrating peptide

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Abstract

Development of an intracellular delivery method for functional peptides via cell-penetrating peptides (CPPs) expands peptide use in basic research and therapeutic applications. Although direct conjugation of a functional peptide with a CPP is the simplest method for delivery, this method has not always been reliable. CPPs usually contain several positively charged amino acids that potentially interact non-specifically with negatively charged molecules in cells and subsequently interfere with conjugated functional peptide function. Here we demonstrate a new intracellular delivery method for peptides in which a functional peptide is released from a positively charged CPP via peptide nucleic acids (PNAs). We prepared an 8-mer PNA conjugated to octa-arginine in tandem (PNA1-CPP) and linked its complementary PNA to an autophagy inducing peptide (PNA2-AIP) by solid-phase peptide synthesis. PNA1-CPP and PNA2-AIP formed a 1 : 1 hybrid via PNA1/PNA2 interaction, thereby indirectly but stably connecting the AIP to the CPP. PNA2-AIP was successfully delivered into cells in a hybrid formation-dependent manner and at least some portion of the PNA1-CPP/PNA2-AIP hybrids dissociated into PNA2-AIP and PNA1-CPP inside the cells. Notably, PNA2-AIP delivered to cells induced more autophagy than AIP directly conjugated to CPP (CPP–AIP). Further, the PNA hybrid did not induce significant cell death. These findings indicate that the PNA1/PNA2 hybrid can function as a molecular glue enabling the delivery of functional peptides into cells.

Graphical abstract: Intracellular delivery of a peptide nucleic acid-based hybrid of an autophagy inducing peptide with a cell-penetrating peptide

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Supplementary files

Article information


Submitted
30 Nov 2019
Accepted
19 Feb 2020
First published
25 Feb 2020

Org. Biomol. Chem., 2020,18, 1978-1986
Article type
Paper

Intracellular delivery of a peptide nucleic acid-based hybrid of an autophagy inducing peptide with a cell-penetrating peptide

Y. Hakata, S. Ishikawa, T. Ohtsuki, M. Miyazawa and M. Kitamatsu, Org. Biomol. Chem., 2020, 18, 1978
DOI: 10.1039/C9OB02559F

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