Tuning Molecular Recognition of RNA and DNA via Sugar Modification

Abstract

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 ...

Ätiologie potentiell primordialer Biomolekül‐Strukturen: Vom Vitamin B12zu den Nukleinsäuren und der Frage nach der Chemie der Entstehung des Lebens – ein Rückblick

“…Oligonukleotidsysteme wie Bicyclo-DNA, HNA und LNA, und darüber hinaus auch zahlreiche weitere Paarungssysteme, deren Synthese mit medizinalchemischer Zielsetzung durch das Präorganisationskriterium stimuliert wurde, [94,104,107,108,111,[113][114][115] haben keinen direkten Bezug zur ätiologischen Problematik; sie alle sind künstliche Systeme, deren Konstitution die für "potentiell natürliche" Nukleinsäure-Alternativen zu fordernden Kriterien (vgl. oben) nicht erfüllt.…”

“…Wie schon angedeutet, reicht die strukturelle Palette der Watson-Crick-Systeme weit über den Strukturtyp der oligomeren Phosphodiester hinaus; dies haben vor allem Untersuchungen gezeigt, die im Laufe der letzten beiden Jahrzehnte in medizinalchemisch orientierten Laboratorien im Hinblick auf die medizinischen Perspektiven des Antisense-Konzepts [228] durchgeführt wurden. [104,107,113,189] Entscheidend Präbiotische Chemie Angewandte Chemie war die Entdeckung der Eigenschaften der bereits erwähnten "PNA" durch Peter Nielsen. [188] Über eine mçglichst umfassende Übersicht auf die Strukturtypen informationeller Oligomersysteme zu verfügen, wäre aus medizinalchemischen, rein chemischen und schließlich vor allem auch ätiologischen Beweggründen wünschenswert.…”

yDNA versus xDNA Pyrimidine Nucleobases: Computational Evidence for Dependence of Duplex Stability on Spacer Location

“…When Watson and Crick unlocked the structure of DNA, many new research fields quickly emerged that focused on applications of modified DNA components . For example, oligonucleotides with modified sugar−phosphate backbones have been extensively studied for use as antisense therapeutics, − which target mRNA using complementary single-stranded oligomers. Modifications to the backbone, such as locked sugars , or phosphorothioate linkages, have proven promising in these applications due to improved stability and cellular uptake, as well as decreased toxicity, when compared with natural oligonucleotides.…”

ChemInform Abstract: Crystallographic Studies of Chemically Modified Nucleic Acids: A Backward Glance

“…Bicyclo-and Tricyclo-DNA. -DNA Analogs with bicyclic and tricyclic sugar moieties were studied by the Leumann group (University of Bern) to analyze the effects of restricted conformational flexibility on nucleic acid-pairing stability [118]. Provided that the analogs conformation is preorganized for the target strand, the stability of the duplex formed should be affected favorably (i.e., by reducing the loss of entropy upon duplex formation).…”