Highly-Efficient Cellular Uptake and Membrane Permeability of Cell-Penetrating Peptides via Introduction of Homoarginine Residues
Abstract
The use of cell-penetrating peptides (CPPs) for the intracellular delivery of pharmaceuticals has progressed from basic research to global clinical studies. In this study, we investigated the effects of introducing l-homoarginine into the CPP oligoarginine on intracellular uptake and membrane permeability efficiency. We demonstrated that extending the arginine side chain by one methylene group (l-homoarginine) significantly increased the intracellular uptake of hexa-oligoarginine compared with extension of the main chain by one carbon atom (l-β-homoarginine). Incorporation of the l-homoarginine sequence improved the short-term stability of hexa-oligoarginine in fetal bovine serum. Furthermore, this strategy showed potential utility in boron neutron capture therapy; when used as an intracellular delivery vehicle, the l-homoarginine-containing peptide facilitated the intracellular delivery of therapeutic boron-containing agents and the effects of thermal neutron irradiation, resulting in increased cancer cell killing. These findings demonstrate that the introduction of l-homoarginine residues is an effective approach for improving the intracellular delivery efficiency and biological stability of CPPs.
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BibTeX
@article{taniyama2026highlyefficient,
title = {{Highly-Efficient Cellular Uptake and Membrane Permeability of Cell-Penetrating Peptides via Introduction of Homoarginine Residues}},
author = {Ryunosuke Taniyama and Daisuke Fujiwara and Yoshihide Hattori and Masataka Michigami and Kentarou Sakamoto and Tomoka Takatani-Nakase and Mitsunori Kirihata and Ikuo Fujii and Ikuhiko Nakase},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = sep,
doi = {10.1248/bpb.b26-00374},
url = {https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00374/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Highly-Efficient Cellular Uptake and Membrane Permeability of Cell-Penetrating Peptides via Introduction of Homoarginine Residues
AU - Ryunosuke Taniyama
AU - Daisuke Fujiwara
AU - Yoshihide Hattori
AU - Masataka Michigami
AU - Kentarou Sakamoto
AU - Tomoka Takatani-Nakase
AU - Mitsunori Kirihata
AU - Ikuo Fujii
AU - Ikuhiko Nakase
PY - 2026
DA - 2026/09/12
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b26-00374
UR - https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00374/_article
AB - The use of cell-penetrating peptides (CPPs) for the intracellular delivery of pharmaceuticals has progressed from basic research to global clinical studies. In this study, we investigated the effects of introducing l-homoarginine into the CPP oligoarginine on intracellular uptake and membrane permeability efficiency. We demonstrated that extending the arginine side chain by one methylene group (l-homoarginine) significantly increased the intracellular uptake of hexa-oligoarginine compared with extension of the main chain by one carbon atom (l-β-homoarginine). Incorporation of the l-homoarginine sequence improved the short-term stability of hexa-oligoarginine in fetal bovine serum. Furthermore, this strategy showed potential utility in boron neutron capture therapy; when used as an intracellular delivery vehicle, the l-homoarginine-containing peptide facilitated the intracellular delivery of therapeutic boron-containing agents and the effects of thermal neutron irradiation, resulting in increased cancer cell killing. These findings demonstrate that the introduction of l-homoarginine residues is an effective approach for improving the intracellular delivery efficiency and biological stability of CPPs.
SN - 1347-5215
SN - 0918-6158
ER -