Chemical Regulation of DNA i‐Motifs for Nanobiotechnology and Therapeutics

Debnath, Manish; Fatma, Khushnood; Dash, Jyotirmayee

doi:10.1002/anie.201813288

Cited by 65 publications

(41 citation statements)

References 154 publications

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“…Both the nanofibrous structure and the rheological results confirmed that the formed solid DNAm aterials were hydrogels. [12] Remarkably,t he G' value and G'' value reached 9 10 4 Pa and 2 10 4 Pa, respectively ( Figure 2G), which were much higher than that of almost all the previously reported pure DNAh ydrogels. [12d, 19] Fort he underlying mechanism, we speculated that the unique condensing fibrous structure of the hydrogel might be responsible for the high mechanical strength ( Figure S5).…”

Section: Resultsmentioning

confidence: 65%

“…[11] In particular,the imotif DNAused in this study is aDNA quadruplex structure stabilized by hemi-protonated cytosine-cytosine + (C:C + )base pairs in acidic medium, which has been widely applied in the preparation of dynamic self-assembled structures. [12] Herein, we designed and synthesized ad ouble-stranded DNA (dsDNA) that was capable of forming i-motif DNAa s building unit, and by using the dsDNA, we constructed ad ynamic DNAs elf-assembly system which achieved lysosomal acidic stimuli specifically mediated topological transformation from nanoparticles to ap hase separated and organelle-like hydrogel architecture in living cells.The effects of the organelle-like hydrogel architecture on behaviors of both cancer and normal cells were investigated.…”

Section: Introductionmentioning

confidence: 99%

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Construction of Organelle‐Like Architecture by Dynamic DNA Assembly in Living Cells

Guo

Liu

et al. 2020

Angewandte Chemie

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The design of controllable dynamic systems is vital for the construction of organelle-like architectures in living cells,b ut has proven difficult due to the lack of control over defined topological transformation of self-assembled structures.H erein, we report aD NA based dynamic assembly system that achieves lysosomal acidic microenvironment specifically inducing topological transformation from nanoparticles to organelle-like hydrogel architecture in living cells. Designer DNAn anoparticles are constructed from doublestranded DNAwith cytosine-richstick ends (C-monomer) and are internalizedi nto cells through lysosomal pathway.T he lysosomal acidic microenvironment can activate the assembly of DNAm onomers,i nducing transformation from nanoparticles to micro-sized organelle-like hydrogel which could further escape into cytoplasm. We show how the hydrogel regulates cellular behaviors:c ytoskeleton is deformed, cell tentacles are significantly shortened, and cell migration is promoted.

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Section: Resultsmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Construction of Organelle‐Like Architecture by Dynamic DNA Assembly in Living Cells

Guo

Liu

et al. 2020

Angewandte Chemie

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“…However, recent studies have shown that i-motif can exist under neutral or physiological pH under molecular crowding conditions or in the presence of some cations [7,8]. I-motif structure might play important regulatory roles in biological processes, such as DNA replication, gene transcription, and maintenance of genomic stability [9]. Some i-motif I-motif structure might play important regulatory roles in biological processes, such as DNA replication, gene transcription, and maintenance of genomic stability [9].…”

Section: Introductionmentioning

confidence: 99%

“…I-motif structure might play important regulatory roles in biological processes, such as DNA replication, gene transcription, and maintenance of genomic stability [9]. Some i-motif I-motif structure might play important regulatory roles in biological processes, such as DNA replication, gene transcription, and maintenance of genomic stability [9]. Some imotif structures in oncogene promoters have been indicated for regulating gene transcriptions, including PDGFR-β, c-myc, BCL2, and KRAS [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Oleanolic Acid Derivatives as Selective Vascular Endothelial Growth Factor Promoter i-Motif Ligands

Zeng

Kang

Zhang

et al. 2021

IJMS

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Vascular endothelial growth factor (VEGF) is an angiogenic growth factor and plays a key role in tumor progression. The C-rich DNA sequence of VEGF promoter can form i-motif structure, which is a potential target for the development of novel anticancer agents. However, there is a limited number of chemotypes as the selective ligands of VEGF promoter i-motif, which leaves much room for development. Herein, we report the discovery of the natural oleanolic acid scaffold as a novel chemotype for the development of selective ligands of VEGF i-motif. A series of oleanolic acid derivatives as VEGF promoter i-motif ligands were synthesized. Subsequent evaluations showed that 3c could selectively bind to and stabilize VEGF promoter i-motif without significant binding to G-quadruplex, duplex DNA, and other oncogene i-motifs. Cell-based assays indicated that 3c could effectively downregulate VEGF gene transcription and expression in MCF-7 cells, inhibit tumor cells proliferation and migration, and induce cancer cells apoptosis. This work provides evidence of VEGF promoter i-motif as an anticancer target and will facilitate future efforts for the discovery of oleanolic acid-based selective ligands of VEGF promoter i-motif.

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“…[14][15][16] The pH responsive structure and reversible conformational switching properties of i-motifs have been potentially used in DNA nanotechnology. [17][18][19][20] However, i-motifs have been less investigated for designing ligands for therapeutics [21][22][23] as compared to complementary G-quadruplexes (G 4 s) that have been well studied in the past decade. [24][25][26] The reported i-motif ligands such as the cationic porphyrin TmPyP4, 27 phenanthroline derivatives, 28 neomycin-perylene conjugates, 29 crystal violet, 30 Thioavin T 31,32 and berberine 33 do not show signicant selectivity for i-motif structures over duplex and quadruplex structures.…”

Section: Introductionmentioning

confidence: 99%

In situ formation of transcriptional modulators using non-canonical DNA i-motifs

et al. 2020

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In situ formation of transcriptional modulators using non-canonical DNA i-motifs i-Motif DNA immobilized magnetic nanoparticles assemble the best binders via selection followed by in situ cycloaddition. The generated i-motif specifi c ligands modulate the transcription of cellular oncogenes.We acknowledge Mr. Gopal Krishna Manna, IACS for his help with the preparation of the cover art.Non-canonical DNA i-motifs and G-quadruplexes are postulated as genetic switches for the transcriptional regulation of proto-oncogenes. However, in comparison to G-quadruplexes, the therapeutic potential of imotifs is less explored. The development of i-motif selective ligands by conventional approaches is challenging due to the structural complexity of i-motifs. The target guided synthetic (TGS) approach involving in situ cycloaddition could provide specific ligands for these dynamic DNA structures. Herein, we have used i-motif forming C-rich DNA and their complementary G-quadruplex forming DNA sequences of c-MYC and BCL2 promoter regions as well as a control self-complementary duplex DNA sequence as the templates to generate selective ligands from a pool of reactive azide-alkyne building blocks. In our approach, thiolated DNA targets are immobilized on the surface of gold-coated iron nanoparticles to enable efficient isolation of the newly generated ligands from the solution mixture by simple magnetic decantation. The combinatorial in situ cycloaddition generated cell-membrane permeable triazole leads for respective DNA targets (c-MYC and BCL2 i-motifs and G-quadruplexes) that selectively promote their formation. In vitro cellular studies reveal that the c-MYC i-motif and Gquadruplex leads downregulate c-MYC gene expression whereas the BCL2 i-motif lead upregulates and the BCL2 G-quadruplex lead represses BCL2 gene expression. The TGS strategy using i-motif DNA nanotemplates represents a promising platform for the direct in situ formation of i-motif specific ligands for therapeutic intervention. Fig. 9 (a-d) qRT-PCR and western blotting analysis results of c-MYC and BCL2 gene expression in HeLa and B95.8 cells after 24 h of treatment with 3be, 3bm, 3ao and 3ap. The in vitro dual luciferase promoter assay for evaluating the effect of the lead ligands on the promoter activity of (e) the c-MYC-FLuc promoter and (f) BCL2-FLuc promoter [*p value is < 0.05].Fig. 10 Proposed model for targeting four-stranded DNA secondary structures within the c-MYC and BCL2 gene promoter regions.This journal is

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Chemical Regulation of DNA i‐Motifs for Nanobiotechnology and Therapeutics

Cited by 65 publications

References 154 publications

Construction of Organelle‐Like Architecture by Dynamic DNA Assembly in Living Cells

Construction of Organelle‐Like Architecture by Dynamic DNA Assembly in Living Cells

Synthesis and Biological Evaluation of Oleanolic Acid Derivatives as Selective Vascular Endothelial Growth Factor Promoter i-Motif Ligands

In situ formation of transcriptional modulators using non-canonical DNA i-motifs

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