Targeting insulin-like growth factor I with 10-23 DNAzymes: 2'-O-methyl modifications in the catalytic core enhance mRNA cleavage

Biochemistry
Alesya A FokinaJean-Christophe François

Abstract

Insulin-like growth factor I (IGF-I) and its cognate receptor (IGF-1R) contribute to normal cell function and to tumorigenesis. The role of IGF-I signaling in tumor growth has been demonstrated in vivo using nucleic acid-based strategies. Here, we designed the first 10-23 DNAzymes directed against IGF-I mRNA. Unlike antisense approaches and RNA interference that require protein catalysis, DNAzymes catalyze protein-free RNA cleavage. We identified target sequences and measured catalytic properties of differently designed DNAzymes on short synthetic RNA targets and on in vitro transcribed IGF-I mRNA. The most efficient cleavers were then transfected into cells, and their inhibitory effect was analyzed using reporter gene assays. We found that increasing the size of DNAzyme flanking sequences and modifications of the termini with 2'-O-methyl residues improved cleavage rates of target RNAs. Modification of the catalytic loop with six 2'-O-methyl ribonucleotides at nonessential positions increased or decreased catalytic efficiency depending on the mRNA target site. In cells, DNAzymes with 2'-O-methyl-modified catalytic cores and flanking sequences were able to inhibit reporter gene activity because of specific recognition and cleava...Continue Reading

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Citations

Mar 17, 2015·Expert Opinion on Biological Therapy·Alesya A FokinaJean-Christophe François
Nov 28, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Marcel Hollenstein
Apr 3, 2014·Chembiochem : a European Journal of Chemical Biology·Carl W BrownSteven W Graves
Jun 4, 2014·Angewandte Chemie·Carl W BrownSteven W Graves
Mar 15, 2015·Bioorganic & Medicinal Chemistry Letters·Feng WangJuewen Liu
May 30, 2016·Trends in Biochemical Sciences·Scott K Silverman
Jun 10, 2017·Chemical Reviews·Wenhu ZhouJuewen Liu
Jul 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hannah RosenbachIngrid Span
Apr 24, 2018·Chembiochem : a European Journal of Chemical Biology·Yukiko KamiyaHiroyuki Asanuma
Feb 15, 2019·Cancer Research·Levon M Khachigian
Mar 27, 2021·Nature Chemistry·Yajun WangJohn C Chaput
Apr 1, 2021·Nature Chemistry·Yifei Zhou, Chuanzheng Zhou

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