Antisense properties of tricyclo-DNA

Renneberg, Dorte; Bouliong, Emilie; Reber, Ulrich; Schümperli, Daniel; Leumann, Christian J.

doi:10.1093/nar/gkf412

Cited by 79 publications

(78 citation statements)

References 36 publications

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“…12d) was therefore necessary in order to block the molecule in the most favorable conformation for DNA-binding. Indeed, tricyclo-DNA analogs of this type are among the most potent tools recently described for inhibiting gene expression 122 and have been successfully used for blocking aberrant splicing, 123 a property shared with other DNA analogs such as PNAs (vide infra).…”

Section: 117mentioning

confidence: 99%

Chirality as a tool in nucleic acid recognition: Principles and relevance in biotechnology and in medicinal chemistry

et al. 2007

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The understanding of the interaction of chiral species with DNA or RNA is very important for the development of new tools in biology and of new drugs. Several cases in which chirality is a crucial point in determining the DNA binding mode are reviewed and discussed, with the aim of illustrating how chirality can be considered as a tool for improving the understanding of mechanisms and the effectiveness of nucleic acid recognition. The review is divided into two parts: the former describes examples of chiral species interacting with DNA: intercalators, metal complexes, and groove binders; the latter part is dedicated to chirality in DNA analogs, with discussion of phosphate stereochemistry and chirality of ribose substitutes, in particular of peptide nucleic acids (PNAs) for which a number of works have been published recently dealing with the effect of chirality in DNA recognition. The discussion is intended to show how enantiomeric recognition originates at the molecular level, by exploiting the enormous progresses recently achieved in the field of structural characterization of complexes formed by nucleic acid with their ligands by crystallographic and spectroscopic methods. Examples of application of the DNA binding molecules described and the role of chirality in DNA recognition relevant for biotechnology or medicinal chemistry are reported.

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Section: 117mentioning

confidence: 99%

Chirality as a tool in nucleic acid recognition: Principles and relevance in biotechnology and in medicinal chemistry

et al. 2007

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“…Lipofectamine-mediated delivery of a 17-mer tricyclo-oligodeoxynucleotide complementary to the cryptic 3ʹ splice site at the beginning of the aberrant exon results in correction of splicing already at nM concentrations with up to 100-fold enhanced efficiency relative to a 2ʹ-OMe-PS-RNA oligonucleotide of the same length and sequence. In contrast to 2ʹ-OMe-PS-RNA, tricyclo-DNA shows antisense activity even in the absence of lipofectamine, albeit only at much higher oligonucleotide concentrations [4].…”

Section: Introductionmentioning

confidence: 90%

Tuning Molecular Recognition of RNA and DNA via Sugar Modification

Leumann¹

2005

Chimia

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This minireview highlights three aspects of our recent work in the area of sugar modified oligonucleotide analogues. It provides an overview over recent results on the conformationally constrained analogue tricyclo-DNA with special emphasis of its antisense properties, it summarizes results on triple-helix forming oligodeoxynucleotides containing pyrrolidino-nucleosides with respect to DNA recognition via the dual recognition mode, and it highlights the advantageous application of the orthogonal oligonucleotidic pairing system homo-DNA in molecular beacons for DNA diagnostics.Keywords: Antisense · DNA recognition · DNA triple-helix · Molecular beacons · Pyrrolidino nucleosides ar, the phosphate and the nucleobase, are equally amenable to chemical modification to improve on desired properties. Modifications at the sugar unit, ranging from simple substitutions at the 2ʹ-hydroxyl group to complete replacement of the sugar by different structural scaffolds have the most profound effect on the pairing properties of derived oligonucleotides. For example, changing the geometry of some of the torsion angles in the backbone, as for example in the case of homo-DNA, bc-DNA or xylo-DNA leads to base association preferences different from that of the Watson-Crick type, or to orthogonal base-pairing systems. On the other side, conformational constriction or preorganization of backbone torsion angles in the sugar unit as in the case of LNA or tricyclo-DNA (tc-DNA) leads to increased complex stability by maintaining the typical Watson-Crick association mode. Therefore understanding the relation between sugar structure and pairing properties in sufficient detail is the key for tuning oligonucleotide properties at will by chemical modification.In the following we concentrate on three different sugar modifications that we have recently investigated in three different contexts. First we summarize recent results with conformationally constrained oligonucleotides showing increased RNA affinity, then we focus on a combination of specific base and unspecific phosphate recognition as a means to increase triple-helix stability, and in the last section we give an example on how orthogonal oligonucleotidic basepairing systems that do not cross-pair with natural nucleic acids, can advantageously be used in biotechnology. Conformationally Constrained Oligonucleotides for RNA RecognitionOver the last years we developed the DNA analogue tricyclo-(tc)DNA (Fig. 1). As LNA, tc-DNA belongs to the class of conformationally constrained oligonucleotide analogues. These were specifically designed to increase complementary RNA or DNA affinity by reducing the entropy change upon duplex formation via structural preorganization of the single strand. We reported in the past on the synthesis and duplex formation properties of tricyclo-DNA and found indeed reduced entropy changes upon duplex formation and increased thermostability of duplexes with RNA by 2-4 °C in melting temperature per modification relative to DNA [2] [3]. With this it is one of ...

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“…Les AON-tcDNA, analogues synthétiques de l'ADN, s'hybrident avec une très haute affinité avec leurs ARN pré-messagers cibles afin d'en moduler l'épissage et restaurer un cadre de lecture opérationnel éventuel-lement perturbé par une mutation [6,7] (Figure 1). Dans le cas de la souris mdx (modèle murin de DMD), ils permettent la synthèse d'une dystrophine certes tronquée, mais suffisamment stable et fonctionnelle pour entraîner un bénéfice thérapeutique.…”

Section: Une Nouvelle Génération D'oligonucléotides Antisensunclassified