Synthesis and properties of DNA oligonucleotides with a zwitterionic backbone structure

Schmidtgall, Boris; Spork, Anatol P.; Wachowius, Falk; Höbartner, Claudia; Ducho, Christian

doi:10.1039/c4cc06371f

Cited by 14 publications

(39 citation statements)

References 28 publications

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“…Instead of a triazole, introduction of nucleosyl-3′ amido methyl amino linkages yields a zwitterionic backbone that can hybridize with normal DNA, sensitive to mismatches [104]. For siRNA applications, RNA oligomers with neutral phosphodiester-thioester linkages displayed serum stability, albumin binding, cellular uptake, intracellular hydrolysis to normal RNA phosphodiesters, and RNAi activity in mouse livers [105].…”

Section: Other Backbone Modificationsmentioning

confidence: 99%

DNA and RNA derivatives to optimize distribution and delivery

Wickstrom

2015

Advanced Drug Delivery Reviews

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SUMMARY Synthetic, complementary DNA single strands and short interfering RNA double strands have been found to inhibit the expression of animal, plant, and viral genes in cells, animals, and patients, in a dose dependent and sequence specific manner. DNAs and RNAs, however, are readily digested in biological systems. Hence, chemists are obliged to design and synthesize nuclease-resistant analogs of normal DNA (Fig. 1).

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Section: Other Backbone Modificationsmentioning

confidence: 99%

DNA and RNA derivatives to optimize distribution and delivery

Wickstrom

2015

Advanced Drug Delivery Reviews

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“…These considerations have led to our recently reported design of a novel artificial internucleotide linkage named 'NAA-modification' ( Fig. 1 ) [ 38 ]. Ongoing synthetic and structure-activity relationship (SAR) studies on naturally occurring muraymycin antibiotics (e.g., muraymycin A1 ( 1 )) [ 39 – 46 ] have led to our previously reported synthesis of 'nucleosyl amino acid' structures 2 [ 47 – 48 ] as simplified 5'-defunctionalized analogues of the muraymycin core motif.…”

Section: Introductionmentioning

confidence: 99%

“… Design concept of nucleosyl amino acid (NAA)-modified oligonucleotides 5 formally derived from structures 1 – 4 (B 1 , B 2 = nucleobases); previously employed 'dimeric' T–T phosphoramidites 6 [ 38 ] for the automated synthesis of NAA-modified oligonucleotides; new 'dimeric' A–T phosphoramidites 7 as target structures of this study (DMTr = 4,4'-dimethoxytrityl). …”

Section: Introductionmentioning

confidence: 99%

“…We have previously described that NAA-modified DNA oligonucleotides can be obtained by standard solid phase-supported automated DNA synthesis, using the 'dimeric' phosphoramidite building blocks 6 ( Fig. 1 ) [ 38 ]. Overall, 24 different oligonucleotide sequences with one to four NAA-modifications at various positions were synthesized.…”

Section: Introductionmentioning

confidence: 99%

“…Overall, we found that NAA-modified DNA oligonucleotides (i) formed stable duplexes with complementary counterstrands; (ii) were fully capable of mismatch discrimination and (iii) formed duplexes without significant structural distortion, i.e., B-form helices (DNA/DNA duplexes) and A-form helices (DNA/RNA duplexes), respectively. It was concluded that typical chemical properties of nucleic acids are retained in NAA-modified DNA oligonucleotides [ 38 ], thus making the NAA-linkage an interesting structural motif for oligonucleotide analogues.…”

Section: Introductionmentioning

confidence: 99%

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NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

Schmidtgall¹,

Höbartner²,

Ducho³

2015

Beilstein J. Org. Chem.

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SummaryModifications of the nucleic acid backbone are essential for the development of oligonucleotide-derived bioactive agents. The NAA-modification represents a novel artificial internucleotide linkage which enables the site-specific introduction of positive charges into the otherwise polyanionic backbone of DNA oligonucleotides. Following initial studies with the introduction of the NAA-linkage at T–T sites, it is now envisioned to prepare NAA-modified oligonucleotides bearing the modification at X–T motifs (X = A, C, G). We have therefore developed the efficient and stereoselective synthesis of NAA-linked 'dimeric' A–T phosphoramidite building blocks for automated DNA synthesis. Both the (S)- and the (R)-configured NAA-motifs were constructed with high diastereoselectivities to furnish two different phosphoramidite reagents, which were employed for the solid phase-supported automated synthesis of two NAA-modified DNA oligonucleotides. This represents a significant step to further establish the NAA-linkage as a useful addition to the existing 'toolbox' of backbone modifications for the design of bioactive oligonucleotide analogues.

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Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA‐Gapmer Approach

et al. 2020

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Oligonucleotides (ON) are promising therapeutic candidates, for instance by blocking endogenous mRNA (antisense mechanism). However, ON usually require structural modifications of the native nucleic acid backbone to ensure satisfying pharmacokinetic properties. One such strategy to design novel antisense oligonucleotides is to replace native phosphate diester units by positively charged artificial linkages, thus leading to (partially) zwitterionic backbone structures. Herein, we report a "gapmer" architecture comprised of one zwitterionic central segment ("gap") containing nucleosyl amino acid (NAA) modifications and two outer segments of locked nucleic acid (LNA). This NAA/LNA-gapmer approach furnished a partially zwitterionic ON with optimised properties: i) the formation of stable ON-RNA duplexes with base-pairing fidelity and superior target selectivity at 37°C; and ii) excellent stability in complex biological media. Overall, the NAA/LNA-gapmer approach is thus established as a strategy to design partially zwitterionic ON for the future development of novel antisense agents.

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Synthesis and properties of DNA oligonucleotides with a zwitterionic backbone structure

Cited by 14 publications

References 28 publications

DNA and RNA derivatives to optimize distribution and delivery

DNA and RNA derivatives to optimize distribution and delivery

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA‐Gapmer Approach

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