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Title: Endowment of pH responsivity to anticancer peptides by introducing 2,3‐diaminopropionic acid residues
Authors: Tanishiki, Naoto
Yano, Yoshiaki
Matsuzaki, Katsumi
Author's alias: 矢野, 義明
松﨑, 勝巳
Keywords: amino acids
antitumor agents
pH responsivity
Issue Date: 16-Aug-2019
Publisher: Wiley
Journal title: ChemBioChem
Volume: 20
Issue: 16
Start page: 2109
End page: 2117
Abstract: Endowment of pH responsivity to anticancer peptides is a promising approach to achieve better selectivity to cancer tissues. In this research, a template peptide was designed based on magainin 2, an antimicrobial peptide with anticancer activity, and a series of peptides were designed by replacing different numbers of lysine with the unnatural amino acid, 2, 3‐diaminopropionic acid (Dap), which has a positive charge at weakly acidic pH in cancer tissues, but is neutral at physiological pH 7.4. These Dap‐containing peptides are expected to interact more strongly with tumor cells than with normal cells because 1) a weakly acidic condition is formed in tumors, and 2) the membrane of tumor cells is more anionic than that of normal cells. While all examined peptides showed potent cytotoxicities to multidrug‐resistant cancer cells at a weakly acidic pH (ED₅₀ ~5 μM), the toxicity was decreased with an increase in the number of Dap at pH 7.4 (8 Dap residues resulted in ED₅₀ ~60 μM). Furthermore, the introduction of Dap reduced cytotoxicity against normal cells. Thus, Dap introduction significantly improved cancer targeting due to a pH‐dependent charge shift. Fluorescence imaging and model membrane experiments supported this charge shift model.
Rights: This is the peer reviewed version of the following article: [ChemBioChem 20(16) 2109-2117], which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
The full-text file will be made open to the public on 14 August 2020 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
DOI(Published Version): 10.1002/cbic.201900226
PubMed ID: 31161686
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