2‘-<i>O</i>-[2-(Guanidinium)ethyl]-Modified Oligonucleotides:  Stabilizing Effect on Duplex and Triplex Structures

Tp, Prakash; Püschl, Ask; Lesnik, Elena A.; Mohan, .; Tereshko,; Egli, Martin; Manoharan, Muthiah

doi:10.1021/ol049470e

Cited by 59 publications

(50 citation statements)

References 19 publications

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“…Strategies have included the incorporation of amino groups prone to protonation under physiological conditions or of the guanidinium group (pK a 12.5), which is highly basic and positively charged over a wide pH range. [17,[22][23][24] In particular, deoxynucleic guanidine (DNG) oligomers in which the internucleoside phosphate linkages have been replaced by cationic guanidinium groups have been extensively studied. [10,25] These DNG analogues are resistant to nucleases and bind to complementary DNA sequences with high affinity without compromising the specificity of binding.…”

Section: Introductionmentioning

confidence: 99%

Impact of the Guanidinium Group on Hybridization and Cellular Uptake of Cationic Oligonucleotides

et al. 2006

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The grafting of cationic groups to synthetic oligonucleotides (ONs) in order to reduce the charge repulsion between the negatively charged strands of a duplex or triplex, and consequently to increase a complex's stability, has been extensively studied. Guanidinium groups, which are highly basic and positively charged over a wide pH range, could be an efficient ON modification to enhance their affinity for nucleic acid targets and to improve cellular uptake. A straightforward post-synthesis method to convert amino functions attached to ONs (on sugar, nucleobase or backbone) into guanidinium tethers has been perfected. In comparison to amino groups, such cationic groups anchored to alpha-oligonucleotide phosphoramidate backbones play important roles in duplex stability, particularly with RNA targets. This high affinity could be explained by dual recognition resulting from Watson-Crick or Hoogsteen base pairing combined with cationic/anionic backbone recognition between strands involving H-bond formation and salt bridging. Molecular-dynamics simulations corroborate interactions between the cationic backbones of the alpha-ONs and the anionic backbones of the nucleic acid targets. Moreover, ONs with guanidinium modification increased cellular uptake relative to negatively charged ONs. The cellular localization of these new cationic phosphoramidate ONs is mainly cytoplasmic. The uptake of these ON analogues might occur through endocytosis.

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Section: Introductionmentioning

confidence: 99%

Impact of the Guanidinium Group on Hybridization and Cellular Uptake of Cationic Oligonucleotides

et al. 2006

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“…For example, the gauche effect between O4′ and O2′ that drives the sugar conformational equilibrium toward the C3′- endo side is enhanced by the presence of electronegative atoms or groups in the substituent, as recently demonstrated by extensive analyses of the influence of the chemistry of RNA 2′- O -substituents on the stability of duplexes (37,39,42–44). Combining the 2-thio and 2′- O -MOE modifications generates synergistic stereoelectronic effects that are absent, e.g.…”

Section: Discussionmentioning

confidence: 95%

Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2'-O-[2-(methoxy)ethyl]-2-thiothymidines

Diop-Frimpong

Prakash²,

Rajeev³

et al. 2005

Nucleic Acids Research

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Substitution of oxygen atoms by sulfur at various locations in the nucleic acid framework has led to analogs such as the DNA phosphorothioates and 4′-thio RNA. The phosphorothioates are excellent mimics of DNA, exhibit increased resistance to nuclease degradation compared with the natural counterpart, and have been widely used as first-generation antisense nucleic acid analogs for applications in vitro and in vivo. The 4′-thio RNA analog exhibits significantly enhanced RNA affinity compared with RNA, and shows potential for incorporation into siRNAs. 2-Thiouridine (s2U) and 5-methyl-2-thiouridine (m5s2U) are natural nucleotide analogs. s2U in tRNA confers greater specificity of codon–anticodon interactions by discriminating more strongly between A and G compared with U. 2-Thio modification preorganizes the ribose and 2′-deoxyribose sugars for a C3′-endo conformation, and stabilizes heteroduplexes composed of modified DNA and complementary RNA. Combination of the 2-thio and sugar 2′-O-modifications has been demonstrated to boost both thermodynamic stability and nuclease resistance. Using the 2′-O-[2-(methoxy)ethyl]-2-thiothymidine (m5s2Umoe) analog, we have investigated the consequences of the replacement of the 2-oxygen by sulfur for base-pair geometry and duplex conformation. The crystal structure of the A-form DNA duplex with sequence GCGTAT*ACGC (T* = m5s2Umoe) was determined at high resolution and compared with the structure of the corresponding duplex with T* = m5Umoe. Notable changes as a result of the incorporation of sulfur concern the base-pair parameter ‘opening’, an improvement of stacking in the vicinity of modified nucleotides as measured by base overlap, and a van der Waals interaction between sulfur atoms from adjacent m5s2Umoe residues in the minor groove. The structural data indicate only minor adjustments in the water structure as a result of the presence of sulfur. The observed small structural perturbations combined with the favorable consequences for pairing stability and nuclease resistance (when combined with 2′-O-modification) render 2-thiouracil-modified RNA a promising candidate for applications in RNAi.

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“…11) modifications have been synthesized using a novel protecting-group strategy [45]. This modification enhances the binding affinity of oligonucleotides to RNA ( Table 7) as well as to duplex DNA (DT m 3.28 per modification) [45]. The 2'-O-GE-modified oligonucleotides exhibited exceptional resistance to nuclease degradation.…”

Section: '-O-[2-(methoxy)ethyl] and Relatedmentioning

confidence: 99%

“…The 2'-O-GE-modified oligonucleotides exhibited exceptional resistance to nuclease degradation. The crystal structure of a DNA duplex with a single 2'-O-GE modification in each strand was determined at 1.16 resolutions [45]. There is no report of any biological activity of ASOs containing the 2'-O-GE modification.…”

Section: '-O-[2-(methoxy)ethyl] and Relatedmentioning

confidence: 99%

An Overview of Sugar‐Modified Oligonucleotides for Antisense Therapeutics

Prakash

2011

Chemistry & Biodiversity

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184

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Among the multitude of chemical modifications that have been described over the past two decades, oligonucleotide analogs that are modified at the 2'-position of the furanose sugar have been especially useful for improving the drug-like properties of antisense oligonucleotides (ASOs). These modifications bias the sugar pucker towards the 3'-endo-conformation and improve ASO affinity for its biological target (i.e., mRNA). In addition, antisense drugs incorporating 2'-modified nucleotides exhibit enhanced metabolic stability, and improved pharmacokinetic and toxicological properties. Further conformational restriction of the 2'-substituent to the 4'-position of the furanose ring yielded the 2',4'-bridged nucleic acid (BNA) analogs. ASOs containing BNA modifications showed unprecedented increase in binding affinity for target RNA, while also improved nuclease resistance, in vitro and in vivo potency. Several ASO drug candidates containing 2'-modified nucleotides have entered clinical trials and continue to make progress in the clinic for a variety of therapeutic indications.

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2‘-O-[2-(Guanidinium)ethyl]-Modified Oligonucleotides: Stabilizing Effect on Duplex and Triplex Structures

Cited by 59 publications

References 19 publications

Impact of the Guanidinium Group on Hybridization and Cellular Uptake of Cationic Oligonucleotides

Impact of the Guanidinium Group on Hybridization and Cellular Uptake of Cationic Oligonucleotides

Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2'-O-[2-(methoxy)ethyl]-2-thiothymidines

An Overview of Sugar‐Modified Oligonucleotides for Antisense Therapeutics

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