Integrating Display and Delivery Functionality with a Cell Penetrating Peptide Mimic as a Scaffold for Intracellular Multivalent Multitargeting

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• 作者：Yugang Bai ; Lien Nguyen ; Ziyuan Song ; Shaohong Peng ; JuYeon Lee ; Nan Zheng ; Iti Kapoor ; Lauren D. Hagler ; Kaimin Cai ; Jianjun Cheng ; H. Y. Edwin Chan ; Steven C. Zimmerman
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：August 3, 2016
• 年：2016
• 卷：138
• 期：30
• 页码：9498-9507
• 全文大小：747K
• 年卷期：0
• ISSN：1520-5126

文摘

The construction of a multivalent ligand is an effective way to increase affinity and selectivity toward biomolecular targets with multiple-ligand binding sites. Adopting this strategy, we used a known cell-penetrating peptide (CPP) mimic as a scaffold to develop a series of multivalent ligand constructs that bind to the expanded dCTG (CTG^exp) and rCUG nucleotide repeats (CUG^exp) known to cause myotonic dystrophy type I (DM1), an incurable neuromuscular disease. By assembling this polyvalent construct, the hydrophobic ligands are solubilized and delivered into cell nuclei, and their enhanced binding affinity leads to the inhibition of ribonuclear foci formation and a reversal of splicing defects, all at low concentrations. Some of the multivalent ligands are shown to inhibit selectively the in vitro transcription of (CTG·CAG)₇₄, to reduce the concentration of the toxic CUG RNA in DM1 model cells, and to show phenotypic improvement in vivo in a Drosophila model of DM1. This strategy may be useful in drug design for other trinucleotide repeat disorders and more broadly for intracellular multivalent targeting.