Design, Synthesis and Functional Analysis of Dansylated Polytheonamide Mimic: An Artificial Peptide Ion Channel.
J Am Chem Soc. 2012 Aug 4;
Authors: Itoh H, Matsuoka S, Kreir M, Inoue M
Abstract
We report herein the design, total synthesis and functional analysis of a novel artificial ion channel molecule, designated as dansylated polytheonamide mimic (3). The channel 3 was designed based on an exceptionally potent cytotoxin, polytheonamide B (1). Our strategy for the development of synthetic ion channels, which could be easily derivatized for various functions, involved two key features. First, the structure of 1 was simplified by replacing many of non-proteinogenic amino acid residues which required multi-step synthesis by commercially available amino acids while retaining those residues necessary for folding. It significantly reduced the number of synthetic steps and facilitated a practical chemical construction of 3. Secondly, the introduction of propargyl glycine at residue 44 enabled facile installation of dansyl group as a reporter of the membrane localization of 3. Application of a newly designed protective group strategy provided efficient construction of the 37 amino acid sequence of residues 12-48 through one automatic solid-phase peptide synthesis. After peptide cleavage from the resin, 3 was synthesized via dansyl group introduction and one fragment-coupling reaction with residues 1-11, followed by the global deprotection. The simplified mimic 3 exhibited potent cytotoxicity toward p388 mouse leukemia cells (IC50 = 12 nM), effectively induced ion transport across the lipid bilayers of liposomes, and displayed H+ and Na+ ion channel activities. Because of its simplified yet functional scaffold structure with a potential for diversification, our rationally designed ion channel molecule should be useful as a novel platform for developing various cytotoxic channel molecules with additional desired functions.
PMID: 22861006 [PubMed - as supplied by publisher]
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