Oligonucleotide–polyamine conjugates: Influence of length and position of 2′-attached polyamines on duplex stability and antisense effect

Winkler, Johannes; Saadat, Karmin; Díaz‐Gavilán, Mónica; Urban, Ernst; Noe, Christian R.

doi:10.1016/j.ejmech.2008.05.012

Cited by 29 publications

(23 citation statements)

References 34 publications

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“…Inclusion of carbamoyl-linked linear polyamines at the 3´-terminal nucleotides of PS-modified ODNs ( Table 2; structures 15-18) either decreased, or had no effect on duplex formation with complementary RNA or DNA targets [59]. Unexpectedly, however, both spermine and pentamine-ODNs (structures 17 and 18, respectively) proved superior to unmodified ASOs in downregulating BCL-2 protein in human melanoma cells (100 nM treatment for 48 h).…”

Section: Sugar-modified Polyamine-oligonucleotide Conjugatesmentioning

confidence: 96%

“…However, in contrast to the terminal positions of oligonucleotides, the stability of ODN-DNA and ODN-RNA duplexes is very sensitive to modifications of the ribose structure and conformation. Although most investigations have focused on the conjugation of amines and polyamines to the 2´-O positions of riboses of ODNs and oligoribonucleotides (ORNs) with various linkers ( Table 2; structures 6-18) [34,[48][49][50][51][52][53][54][55][56][57][58][59][60][61], in one study the C-4´ position of a deoxyribose was used to conjugate aminoalkyl groups ( Table 2; structures 19-20) [60]. Incorporation of 4´-aminomethyl, -ethyl-and -propyl-groups into ODNs at various positions slightly increased melting temperatures of duplexes formed with a complementary DNA target by 0.5-1°C per modification.…”

Section: Sugar-modified Polyamine-oligonucleotide Conjugatesmentioning

confidence: 99%

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Polyamine–Oligonucleotide Conjugates: A Promising Direction for Nucleic Acid Tools and Therapeutics

2015

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Chemical modification and/or the conjugation of small functional molecules to oligonucleotides have significantly improved their biological and biophysical properties, addressing issues such as poor cell penetration, stability to nucleases and low affinity for their targets. Here, the authors review the literature reporting on the biophysical, biochemical and biological properties of one particular class of modification - polyamine-oligonucleotide conjugates. Naturally derived and synthetic polyamines have been grafted onto a variety of oligonucleotide formats, including antisense oligonucleotides and siRNAs. In many cases this has had beneficial effects on their properties such as target hybridization, nuclease resistance, cellular uptake and activity. Polyamine-oligonucleotide conjugation, therefore, represents a promising direction for the further development of oligonucleotide-based therapeutics and tools.

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Section: Sugar-modified Polyamine-oligonucleotide Conjugatesmentioning

confidence: 96%

Section: Sugar-modified Polyamine-oligonucleotide Conjugatesmentioning

confidence: 99%

Polyamine–Oligonucleotide Conjugates: A Promising Direction for Nucleic Acid Tools and Therapeutics

2015

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“…Optimization of tumor-targeted siRNA delivery is possible by DARPin affinity maturation and/or multimerization, by modification of the siR-NA itself (6,41) and by new approaches that help improving the translocation of siRNA from endosomes into the cytoplasm. NOTE: Treatment was done as described in the legend to Fig.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins

Winkler

Martin-Killias

Plückthun

et al. 2009

Molecular Cancer Therapeutics

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Specific delivery to tumors and efficient cellular uptake of nucleic acids remain major challenges for gene-targeted cancer therapies. Here we report the use of a designed ankyrin repeat protein (DARPin) specific for the epithelial cell adhesion molecule (EpCAM) as a carrier for small interfering RNA (siRNA) complementary to the bcl-2 mRNA. For charge complexation of the siRNA, the DARPin was fused to a truncated human protamine-1 sequence. To increase the cell binding affinity and the amount of siRNA delivered into cells, DARPin dimers were generated and used as fusion proteins with protamine. All proteins expressed well in Escherichia coli in soluble form, yet, to remove tightly bound bacterial nucleic acids, they were purified under denaturing conditions by immobilized metal ion affinity chromatography, followed by refolding. The fusion proteins were capable of complexing four to five siR-NA molecules per protamine, and fully retained the binding specificity for EpCAM as shown on MCF-7 breast carcinoma cells. In contrast to unspecific LipofectAMINE transfection, down-regulation of antiapoptotic bcl-2 using fusion protein complexed siRNA was strictly dependent on EpCAM binding and internalization. Inhibition of bcl-2 expression facilitated tumor cell apoptosis as shown by increased sensitivity to the anticancer agent doxorubicin.

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“…In vitro, they stabilize DNA and RNA duplexes [31,32], especially ones with imperfect base pairing [33]. The distance between amino groups of three and four carbon atoms is practically the same as the distance between phosphate anions in the backbone of DNA making polyamines the perfect compounds for creating "zwitterionic" oligonucleotides [27]. It is known that polyamines interact with DNA and RNA in different ways.…”

Section: Introductionmentioning

confidence: 99%

“…The combination of nucleotides with aminoalkyl chains greatly enhances the variety of possible structures as well as their potential application [24]. Thus, oligonucleotides possessing cationic functionalities in addition to the anionic phosphate backbone have been shown to exhibit promising properties [25][26][27][28]. Polyamines, putrescine, spermine and spermidine, are involved in the regulation of gene function [29,30].…”

Section: Introductionmentioning

confidence: 99%

Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides

Brzezinska

Markiewicz

2015

Molecules

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Abstract:The rationale for the synthesis of cationic modified nucleosides is higher expected nuclease resistance and potentially better cellular uptake due to an overall reduced negative charge based on internal charge compensation. Due to the ideal distance between cationic groups, polyamines are perfect counterions for oligodeoxyribonucleotides. We have synthesized non-nucleosidic analogues built from units that carry different diol structures instead of sugar residues and functionalized with polyamines. The non-nucleosidic analogues were attached as internal or 5′-terminal modifications in oligodeoxyribonucleotide strands. The thermodynamic studies of these polyaminooligonucleotide analogues revealed stabilizing or destabilizing effects that depend on the linker or polyamine used.

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Oligonucleotide–polyamine conjugates: Influence of length and position of 2′-attached polyamines on duplex stability and antisense effect

Cited by 29 publications

References 34 publications

Polyamine–Oligonucleotide Conjugates: A Promising Direction for Nucleic Acid Tools and Therapeutics

Polyamine–Oligonucleotide Conjugates: A Promising Direction for Nucleic Acid Tools and Therapeutics

EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins

Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides

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