Zwitterionic oligonucleotides with 2′-O-[3-(N,N-dimethylamino)propyl]-RNA modification: synthesis and properties

Prakash, Thazha P.; Manoharan, Muthiah; Fraser, Allister S.; Kawasaki, Andrew M.; Lesnik, Elena A.; Owens, Stephen R.

doi:10.1016/s0040-4039(00)00703-6

Cited by 43 publications

(26 citation statements)

References 19 publications

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“…Thermodynamic studies have shown that R:DD triple helices have higher thermal stability than D:DD ones (8,(15)(16)(17)(18), whereas similar free energies and equilibrium constants have been found by isothermal titration calorimetry and EDTA cleavage (19,20). Results in our laboratory and others, with third strand sequences containing a variable number of nucleotides with modified bases or backbones, show thus far nonunderstood differences in affinity as a function of the target sequence and the position of the modified nucleosides in the chain (21)(22)(23). Given these data, the question arises whether, upon binding with its target double helix, a TFO containing an intrinsically heterogeneous backbone conformation, allowing for a tailor-made structural fit to the target, could increase the triplex stability compared with a TFO with a homogeneous backbone.…”

supporting

confidence: 61%

Conformational Diversity Versus Nucleic Acid Triplex Stability, a Combinatorial Study

Bernal-Méndez

Leumann

2001

Journal of Biological Chemistry

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The stability of a triple helix formed between a DNA duplex and an incoming oligonucleotide strand strongly depends on the solvent conditions and on intrinsic chemical and conformational factors. Attempts to increase triple helix stability in the past included chemical modification of the backbone, sugar ring, and bases in the third strand. However, the predictive power of such modifications is still rather poor. We therefore developed a method that allows for rapid screening of conformationally diverse third strand oligonucleotides for triplex stability in the parallel pairing motif to a given DNA double helix sequence. Combinatorial libraries of oligonucleotides of the requisite (fixed) base composition and length that vary in their sugar unit (ribose or deoxyribose) at each position were generated. After affinity chromatography against their corresponding immobilized DNA target duplex, utilizing a temperature gradient as the selection criterion, the oligonucleotides forming the most stable triple helices were selected and characterized by physicochemical methods. Thus, a series of oligonucleotides were identified that allowed us to define basic rules for triple helix stability in this conformationally diverse system. It was found that ribocytidines in the third strand increase triplex stability relative to deoxyribocytidines independently of the neighboring bases and position along the strand. However, remarkable sequence-dependent differences in stability were found for (deoxy)thymidines and uridines.Triple-stranded DNA and RNA structures were first discovered in the late fifties by Felsenfeld and Rich (1, 2). In 1986, two independent research groups demonstrated that triplex-forming oligonucleotides (TFOs) 1 can be used to specifically recognize a given sequence in a DNA double helix (3, 4), and thus paved the way for their potential use as therapeutics in the antigene strategy and as tools in molecular biology. Polypyrimidine TFOs bind specifically to complementary poly(Pu)⅐poly(Py) double-helix sequences by formation of Hoogsteen base pairs between thymines or protonated cytosines in the TFO and adenines or guanines, respectively, in the poly(Pu) strand of the DNA double helix. The molecular recognition process is highly sensitive to base mismatches, so that a single duplex site can be targeted within megabase DNA (5-7).It has been shown previously that triplexes not only form within the pure DNA or RNA backbone context but also within mixed RNA and DNA strands, although with distinct differences in stability within a given sequence context (8). Recent analyses by NMR and FT-IR have shown that D:DD and R:DD triple helices (where DD stands for the DNA double helix, and D: or R: for the DNA or RNA TFO, respectively) have heterogeneous backbone conformations, leading to energetically compromised conformations for certain ribo-and deoxyribonucleotides in the three strands (9 -15). Thermodynamic studies have shown that R:DD triple helices have higher thermal stability than D:DD ones (8, 15-18), whereas similar...

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supporting

confidence: 61%

Conformational Diversity Versus Nucleic Acid Triplex Stability, a Combinatorial Study

Bernal-Méndez

Leumann

2001

Journal of Biological Chemistry

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“…The N,N-dimethyl derivative of the 2'-O-AP substitution (Fig. 10) also exhibited similar nuclease resistance and binding affinity ( Table 4) profile [29]. Table 4) are also reported [30].…”

Section: '-O-aminoalkyl Modificationsmentioning

confidence: 73%

2-Modified Oligonucleotides for Antisense Therapeutics

Prakash¹,

Bhat²

2007

CTMC

100

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Chemically modified antisense oligonucleotides are currently progressing in multiple clinical trials. Among several chemical modifications made, modification of the 2'-position has proved most successful. Second generation antisense oligonucleotides incorporating these 2'-modifications exhibit high binding affinity to target RNA, enhanced metabolic stability, and improved pharmacokinetic and toxicity profiles. This is, in part, due to the enhanced biophysical properties of second generation antisense oligonucleotides. 2'-Modifications that influence the sugar to adopt a 3'-endo sugar pucker can improve properties such as affinity. 2'-Modifications that provide a gauche effect and/or a charge effect can play a significant role in the level of nuclease resistance. The heterocyclic base modifications such as 2-thiothymine provides additive effect on the affinity of 2'-F and 2'-O-MOE modifications. This review summarizes the structural and biophysical properties of selected 2'-modified nucleosides which are candidates for use in oligonucleotide therapeutics.

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“…Oligonucleotides having such a positively charged modification exhibit high binding properties towards RNA and DNA and maintain nuclease resistance [4 ± 6]. Among the 2'-O-substituents developed, recently high affinity was found for the aminoethyl [4], aminopropyl [5], and (dimethylamino)propyl [6] derivatives which may form specific contact with a proximal phosphate group in the nucleic-acids duplex. Because of its natural occurrence [7], we studied the effect of the introduction of an additional sugar moiety at the 2'-position of natural ribonucleosides into RNA.…”

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confidence: 99%

Oligonucleotides Containing Disaccharide Nucleosides

Efimtseva

Bobkov

Mikhailov

et al. 2001

HCA

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Disaccharide nucleosides with 2'-O-(d-arabinofuranosyl), 2'-O-(l-arabinofuranosyl), 2'-O-(d-ribopyranosyl), 2'-O-(d-erythrofuranosyl), and 2'-O-(5-azido-5-deoxy-d-ribofuranosyl) substituents were synthesized. These modified nucleosides were incorporated into oligonucleotides (see Table). Single substitution resulted in a DT m of 0.5 to À 1.48 for DNA/RNA and a DT m of À 0.8 to À 4.78 for DNA/DNA duplexes. These disaccharide nucleosides can be well accommodated in RNA/DNA duplexes, and the presence of a NH 2 ÀC(5'') group has a beneficial effect on duplex stability.

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Zwitterionic oligonucleotides with 2′-O-[3-(N,N-dimethylamino)propyl]-RNA modification: synthesis and properties

Cited by 43 publications

References 19 publications

Conformational Diversity Versus Nucleic Acid Triplex Stability, a Combinatorial Study

Conformational Diversity Versus Nucleic Acid Triplex Stability, a Combinatorial Study

2-Modified Oligonucleotides for Antisense Therapeutics

Oligonucleotides Containing Disaccharide Nucleosides

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