title: Integrating Display and Delivery Functionality with a Cell Penetrating Peptide Mimic as a Scaffold for Intracellular Multivalent Multitargeting.
abstract: 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.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Bai
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong , Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Peng
authors.forename: JuYeon
authors.initials: J
authors.lastname: Lee
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Iti
authors.initials: I
authors.lastname: Kapoor
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Hagler
authors.forename: Kaimin
authors.initials: K
authors.lastname: Cai
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong , Shatin, New Territories, Hong Kong SAR, China.
authors.forename: H Y Edwin
authors.initials: HY
authors.lastname: Chan
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001692:Biological Transport; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D057786:Peptidomimetics / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D018911:Trinucleotide Repeats
chemical_list: D057846:Cell-Penetrating Peptides; D008024:Ligands; D057786:Peptidomimetics