Modulation of the Biological Activity of microRNA-210 with Peptide Nucleic Acids (PNAs)

被引：58

作者：

Fabbri, Enrica ^{[1
]}

Manicardi, Alex ^{[3
]}

Tedeschi, Tullia ^{[3
]}

Sforza, Stefano ^{[3
]}

Bianchi, Nicoletta ^{[1
]}

Brognara, Eleonora ^{[1
]}

Finotti, Alessia ^{[2
]}

Breveglieri, Giulia ^{[2
]}

Borgatti, Monica ^{[1
]}

Corradini, Roberto ^{[3
]}

Marchelli, Rosangela ^{[3
]}

Gambari, Roberto ^{[1
,2
]}

机构：

[1] Univ Ferrara, Dept Biochem & Mol Biol, BioPharmaNet, I-44121 Ferrara, Italy

[2] Univ Ferrara, Dept Biochem & Mol Biol, Lab Dev Pharmacol & Pharmacogenom Therapy, Thalassaemia Biotechnol Ctr, I-44121 Ferrara, Italy

[3] Univ Parma, Dept Organ & Ind Chem, Parco Area Sci, I-43124 Parma, Italy

来源：

CHEMMEDCHEM | 2011年 / 6卷 / 12期

关键词：

drug delivery; erythroid differentiation; hemoglobin; microRNAs; peptide nucleic acids; CELL PENETRATING PEPTIDES; HUMAN NEUROBLASTOMA-CELLS; ARGININE-RICH PEPTIDES; DNA-BINDING; ERYTHROID-DIFFERENTIATION; PROGNOSTIC-FACTOR; CYCLE REGULATION; EXPRESSION; HYPOXIA; INHIBITION;

D O I：

10.1002/cmdc.201100270

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we describe the activity of a peptide nucleic acid (PNA) that targets microRNA-210 (miR-210), which is associated with hypoxia and is modulated during erythroid differentiation. PNAs directed against miR-210 were designed to bind with high affinity to the target RNA strand and to undergo efficient uptake in target cells. A polyarginine-PNA conjugate directed against miR-210 (Rpep-PNA-a210) showed both very high affinity for RNA and efficient uptake into target cells without the need for transfection reagents. An unmodified PNA of the same sequence displayed the ability to bind RNA, but cellular uptake was very poor. Consistent with this, only Rpep-PNA-a210 strongly inhibited miR-210 activity, as evaluated by assays on undifferentiated K562 cells and on cells treated with mithramycin, which was found to induce erythroid differentiation and miR-210 overexpression. Targeting miR-210 by Rpep-PNA-a210 resulted in: 1) a decrease in miR-210 levels as measured by RT-PCR, 2) up-regulation of raptor mRNA, 3) a decrease in gamma-globin mRNA, and 4) decreased expression of differentiated functions (i.e., proportion of benzidine-positive cells, content of embryo-fetal hemoglobins). The efficient delivery of anti-miR PNAs through a suitable peptide carrier (Rpep-PNA-a210) leads to the inhibition of miR-210 activity, altering the expression of miR-210-regulated erythroid functions.

引用

页码：2192 / 2202

页数：11

共 68 条

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