Antisense Properties of End-Modified Oligonucleotides Targeted to Ha-<i>ras</i>Oncogene

Saison‐Behmoaras, Tula; Duroux, Isabelle; Thuong, Nguyen T.; Asseline, Ulysse; Hélène, Claude

doi:10.1089/oli.1.1997.7.361

Cited by 10 publications

(2 citation statements)

References 23 publications

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“…DNA oligonucleotides conjugated with intercalator have been shown to be effective antisense molecules. Helene and colleagues prepared end-modified oligonucleotides targeted to Ha-ras oncogene and showed that the oligonucleotides carrying an acridine tail not only protected the modified oligonucleotides from nucleases, but also enhanced the RNaseH cleavage of the target (Saison-Behmoaras et al, 1997). For possible applications of the (iG, iC)-containing oligonucleotide as antisense molecules, such a strategy involving intercalator end-modifications may be used.…”

Section: Interactions Between Intercalators and Ps-duplexmentioning

confidence: 99%

Structural Studies of a Stable Parallel-Stranded DNA Duplex Incorporating Isoguanine:Cytosine and Isocytosine:Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy

Yang

Sugiyama

Ikeda

et al. 1998

Biophysical Journal

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Isoguanine (2-hydroxyladenine) is a product of oxidative damage to DNA and has been shown to cause mutation. It is also a potent inducer of parallel-stranded DNA duplex structure. The structure of the parallel-stranded DNA duplex (PS-duplex) 5'-d(TiGiCAiCiGiGAiCT) + 5'-d(ACGTGCCTGA), containing the isoguanine (iG) and 5-methyl-isocytosine (iC) bases, has been determined by NMR refinement. All imino protons associated with the iG:C, G:iC, and A:T (except the two terminal A:T) basepairs are observed at 2 degrees C, consistent with the formation of a stable duplex suggested by the earlier Tm measurements [Sugiyama, H., S. Ikeda, and I. Saito. 1996. J. Am. Chem. Soc. 118:9994-9995]. All basepairs are in the reverse Watson-Crick configuration. The structural characteristics of the refined PS-duplex are different from those of B-DNA. The PS duplex has two grooves with similar width (7.0 A) and depth (7.7 A), in contrast to the two distinct grooves (major groove width 11.7 A, depth 8.5 A, and minor groove width 5.7 A, depth 7.5 A) of B-DNA. The resonances of the amino protons of iG and C are clearly resolved and observable, but those of the G and iC are very broad and difficult to observe. Several intercalators with different complexities, including ethidium, daunorubicin, and nogalamycin, have been used to probe the flexibility of the backbone of the (iG, iC)-containing PS-duplex. All of them produce drug-induced UV/vis spectra identical to their respective spectra when bound to B-DNA, suggesting that those drugs bind to the (iG, iC)-containing PS-duplex using similar intercalation processes. The results may be useful in the design of intercalator-conjugated oligonucleotides for antisense applications. The study presented in this paper augments our understanding of a growing number of parallel-stranded DNA structures, including the G-quartet, the i-motif, and the unusual homo basepaired parallel-stranded double helix. Their possible relevance is discussed.

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Section: Interactions Between Intercalators and Ps-duplexmentioning

confidence: 99%

Structural Studies of a Stable Parallel-Stranded DNA Duplex Incorporating Isoguanine:Cytosine and Isocytosine:Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy

Yang

Sugiyama

Ikeda

et al. 1998

Biophysical Journal

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“…Other cases of oligos with 3′ or 5′ modifications including dyes, cholesterol (7), or other polymers (8) have shown enhanced antisense binding activities in vitro (9)(10)(11)(12). Recently Agrawal et al (13) have shown that conjugation of dyes, nucleotides, or oligomers through the 5′-position suppresses immunostimulatory activity of CpG containing ODNs, while conjugation at the 3′-position does not.…”

Section: Introductionmentioning

confidence: 99%

A New Platform for Oligonucleotide Delivery Utilizing the PEG Prodrug Approach

et al. 2005

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The oligonucleotide (oligo, ODN), Genasense (GS), an ODN currently waiting for FDA approval, was chosen as a model and modified with a 5' or 3' aminohexyl functionality (1 and 4, respectively) using solid-state synthesis. These amino derivatives were reacted with different releasable PEGs (rPEGs). The in vitro results of the PEG-modified oligos (Table 1) clearly show a substantial increase in rat plasma half-life and enhanced stability against a variety of nucleases, especially the predominant nuclease (PEII) in mammals, which is the main source of oligo degradation in cells. The advantage of using a PEG prodrug approach was further demonstrated by the pharmacokinetic (PK) results, which exhibited much greater C(max), plasma half-life, and area under the curve (AUC) for 3 compared to unmodified GS. A key step in the synthesis of ODN prodrug conjugates with a dye label was also accomplished successfully by employing dihydropyran derivatives of alcohols and acids as orthogonal protecting groups during the synthesis.

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A 5′‐Cap for DNA Probes Binding RNA Target Strands

Egetenmeyer

Richert

2011

Chemistry A European J

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Detecting short RNA strands with high fidelity at any of the bases of their sequence, including the termini, can be challenging, since fraying, wobbling, and refolding all compete with canonical base pairing. We performed a search for 5'-substituents of oligodeoxynucleotides that increase base pairing fidelity at the terminus of duplexes with RNA target strands. From a total of over 70 caps, differing in stacking moiety and linker, a phosphodiester-linked sequence of the residues of L-prolinol, glycine, and oxolinic acid, dubbed ogOA, was identified as a 5'-cap that stabilizes any of the four canonical base pairs, with ΔT(m) values of up to +13.1 °C for an octamer. At the same time, the cap increases discrimination against any of the 12 possible terminal mismatches, including mismatches that are more stable than their perfectly matched counterparts in the control duplex, such as A:A. A probe with the cap also showed increased selectivity in the detection of two closely related microRNAs, let7c and let7a, with a ΔT(m) value of 9.2 °C. Melting curves also yielded thermodynamic data that shed light on the uniformity of molecular recognition in the sequence space of DNA:DNA and DNA:RNA duplexes. Hybridization probes with fidelity-enhancing caps should find applications in the individual and parallel detection of biologically active RNA species.

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Antisense Properties of End-Modified Oligonucleotides Targeted to Ha-rasOncogene

Cited by 10 publications

References 23 publications

Structural Studies of a Stable Parallel-Stranded DNA Duplex Incorporating Isoguanine:Cytosine and Isocytosine:Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy

Structural Studies of a Stable Parallel-Stranded DNA Duplex Incorporating Isoguanine:Cytosine and Isocytosine:Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy

A New Platform for Oligonucleotide Delivery Utilizing the PEG Prodrug Approach

A 5′‐Cap for DNA Probes Binding RNA Target Strands

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