Design, synthesis, and analysis of conformationally constrained nucleic acids

Glick, Gary D.

doi:10.1002/(sici)1097-0282(1998)48:1<83::aid-bip8>3.0.co;2-e

Cited by 36 publications

(22 citation statements)

References 98 publications

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“…In addition, unfavourable conformations (such as strained DNA structures) can be created by connecting the two DNA strands using a covalent linkage which induces distortion of the duplex structures. 12- 15 In previous work, we connected two double helix DNAs with disulfide and bismaleimide linkers and thus controlled the structural arrangement of the duplex using cross-links. [16][17][18][19][20] Further extension of these structural arrangements could be developed for the creation of molecular devices and novel DNA structures, utilizing this DNA cross-linking method.…”

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confidence: 99%

Structural arrangement of DNA constrained by a cross-linker

Endo

Majima

2005

Org. Biomol. Chem.

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confidence: 99%

Structural arrangement of DNA constrained by a cross-linker

Endo

Majima

2005

Org. Biomol. Chem.

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“…In these cases, conformationally constrained oligonucleotides are more suitable models than the pure DNA fragments. 1 Cyclic oligonucleotides are a particular case of constrained oligonucleotides that have been used as models for studying DNA hairpins 2 and quadruplex structures, 3 and have been very useful in many thermodynamic studies. A more general approach to stabilize oligonucleotides is to connect the different strands that make up the structure with a cross-link.…”

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Solution structure and stability of a disulfide cross-linked nucleopeptide duplex

et al. 2003

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NMR methods are used to study the structure and stability of the duplex formed by the nucleopeptide [Ac-Cys-Gly-AlaHse(p 3A dGCATGC)-Ala-OH] 2 [S-S], in which the oligonucleotide is self-complementary and the cysteine residues of the two peptide chains form a disulfide bridge; thermal transitions and NMR-derived structural calculations are consistent with a 3-D structure in which the oligonucleotide forms a standard B-DNA helix without significant distortions; the peptide chains are relatively disordered in solution and lie in the minor groove of the DNA helix; this nucleopeptide duplex exhibits a high melting temperature, indicating that peptide-oligonucleotide conjugates containing cysteines are suitable molecules to establish cross-links between DNA strands and stabilize the duplex.Conformationally constrained oligonucleotides are interesting models for a variety of DNA structures, which include hairpins, cruciforms, triplexes, and so on. In many occasions, these noncanonical DNA structures are difficult to study in short oligonucleotide fragments because of their inherent flexibility. In these cases, conformationally constrained oligonucleotides are more suitable models than the pure DNA fragments. 1 Cyclic oligonucleotides are a particular case of constrained oligonucleotides that have been used as models for studying DNA hairpins 2 and quadruplex structures, 3 and have been very useful in many thermodynamic studies. A more general approach to stabilize oligonucleotides is to connect the different strands that make up the structure with a cross-link. Cross-linked oligonucleotides can be obtained in a variety of ways, but one of the most often used methods is through incorporation of thiol groups and formation of a disulfide bridge. Such an approach has been used to study different constrained DNA 4 and RNA structures. 5 Nucleopeptides are peptide-oligonucleotide conjugates with a covalent phosphodiester bond between the hydroxyl group of an aminoacid side chain and the 3A-or 5A-terminal hydroxyl group of an oligonucleotide chain (Fig. 1A). This kind of bond occurs in some covalently-linked protein-DNA complexes. In addition, the fact that the peptide chain is linked to the 3A-end of the oligonucleotide chain makes these molecules more resistant to exonucleases. 6 Peptide-oligonucleotide conjugates are also interesting because of their pharmaceutical relevance as antisense or antigene compounds. These and other potential applications of these conjugates have been reviewed recently. 7 The aim of this study is to explore the possibility of using peptides to establish a cross-link between opposing DNA strands. In this communication we report on the structure and thermodynamics of the duplex formed by the nucleopeptide [Ac-Cys-Gly-Ala-Hse(p 3A dGCATGC)-Ala-OH] 2 [S-S] (see Fig. 1), in which the two cysteines form a disulfide bond that covalently links the two 3A ends of the oligonucleotide moiety. The DNA sequence is self-complementary, and the peptide is long enough to allow for the crosslinking of the two cys...

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“…Thiol-modified nucleosides developed by Glick and co-workers are compounds bearing a sulphide function on the base [ 103 , 104 ]. They were designed to be incorporated at precise locations within each strand of DNA or RNA in order to form disulfide cross-linked structures and locked, either duplex or hairpin, structures.…”

Section: Structuration Of Nucleic Acids (Cna)mentioning

confidence: 99%

Convertible and Constrained Nucleotides: The 2’-Deoxyribose 5’-C-Functionalization Approach, a French Touch

et al. 2021

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Many strategies have been developed to modulate the biological or biotechnical properties of oligonucleotides by introducing new chemical functionalities or by enhancing their affinity and specificity while restricting their conformational space. Among them, we review our approach consisting of modifications of the 5’-C-position of the nucleoside sugar. This allows the introduction of an additional chemical handle at any position on the nucleotide chain without disturbing the Watson–Crick base-pairing. We show that 5’-C bromo or propargyl convertible nucleotides (CvN) are accessible in pure diastereoisomeric form, either for nucleophilic displacement or for CuAAC conjugation. Alternatively, the 5’-carbon can be connected in a stereo-controlled manner to the phosphate moiety of the nucleotide chain to generate conformationally constrained nucleotides (CNA). These allow the precise control of the sugar/phosphate backbone torsional angles. The consequent modulation of the nucleic acid shape induces outstanding stabilization properties of duplex or hairpin structures in accordance with the preorganization concept. Some biological applications of these distorted oligonucleotides are also described. Effectively, the convertible and the constrained approaches have been merged to create constrained and convertible nucleotides (C2NA) providing unique tools to functionalize and stabilize nucleic acids.

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Design, synthesis, and analysis of conformationally constrained nucleic acids

Cited by 36 publications

References 98 publications

Structural arrangement of DNA constrained by a cross-linker

Structural arrangement of DNA constrained by a cross-linker

Solution structure and stability of a disulfide cross-linked nucleopeptide duplex

Convertible and Constrained Nucleotides: The 2’-Deoxyribose 5’-C-Functionalization Approach, a French Touch

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