Sequence‐Specific Recognition and Modification of Double‐Helical DNA by Oligonucleotides

Abstract

Nucleic acids can be selectively recognized by a large number of natural and synthetic ligands. Oligonucleotides provide the highest specificity of recognition. They can bind to a complementary single-stranded sequence by forming Watson-Crick hydrogen bonds. They can also recognize the major groove of double-helical DNA at specific sequences by forming Hoogsteen or reverse Hoogsteen hydrogen bonds with purine bases of the Watson-Crick base pairs, resulting in a triple helix. Triple-helix formation through oligonucleotide binding to DNA is a sequencespecific interaction involving primarily homopurine . homopyrimidine sequences in the double-helical target. Extending the range of recognition sequences remains a challenge to chemists. Both thermodynamic and kinetic parameters for triplex formation have been determined. These parameters indicate, for example, that triple-helix formation is a much slower process than duplex formation. Nuclease-resistant oligonucleotides synthesized with the aanomers of nucleosides (instead of the natural p-anomers) also form triple helices with doublestranded DNA. Triple-helix-forming oligonucleotides can be modified, for example, by attaching DNA intercalating agents to enhance their binding affinity. They may also be modified with reagents that induce irreversible reactions in their target sequence upon chemical or photochemical activation. Thus, artificial nucleases can be developed with very high sequence specificity on megabase-size DNA. Furthermore, triple-helix-forming oligonucleotides can be used to selectively control gene expression. When bound to the regulatory region(s) of specific genes they may prevent activation (or repression) of transcription. When binding occurs near or downstream from the transcription initiation site, elongation of the transcript may be inhibited. Therefore, the potential exists for developing new gene-blocking agents with therapeutic applications in the treatment of gene disorders.

Interaction between a DNA oligonucleotide and a dinuclear iron(II) supramolecular cylinder; an NMR and molecular dynamics study

“…Indeed synthetic molecules that do achieve sequence selectivity, such as amide linked imidazole/ pyrrole oligomers which bind in the minor groove [2], are rare. Oligonucleotides (synthetic and natural) can selectively recognize DNA by forming triplexes through binding in the major groove [3] and neutral oligonucleotide analogues (e.g. PNAs) can achieve similar effects, although more commonly they achieve sequence selectivity through strand displacement [4].…”

Single strand targeted triplex-formation. Destabilization of guanine quadruplex structures by foldback triplex-forming oligonucleotides

“…In recent years, many groups have investigated the therapeutic potential of oligonucleotides, which results from their ability to selectively interact with genetic material (RNA/IDNA) and interfere with gene expression (1,2). Antisense oligonucleotides are effective against viral and cancer targets both in vitro and in vivo, and human clinical trials are currently underway exploring their possible use as therapies in several diseases (3)(4)(5)(6)(7).…”

“…Antisense oligonucleotides are effective against viral and cancer targets both in vitro and in vivo, and human clinical trials are currently underway exploring their possible use as therapies in several diseases (3)(4)(5)(6)(7). Most of these oligonucleotides are designed to interact with either single-stranded mRNA by Watson-Crick base pairing (antisense approach) or double-stranded DNA by Hoogsteen hydrogen bonding (antigene approach) (1,2). There are few reports on the development of oligonucleotides targeting unusual nucleic acid structures that occur naturally within both RNA and DNA forms (8)(9)(10).…”

Synthesis of the DNA−[Ru(tpy)(dppz)(CH3CN)]2+ Conjugates and Their Photo Cross-Linking Studies with the Complementary DNA Strand

“…Both effects, directed to viral sequences within double-stranded DNA or single-stranded mRNA, allow regulation of gene expression at the stage of transcription (antigene strategy) 10 or translation (antisense strategy). 11 Clearly, highly reactive metal complexes containing reactive ligands should be able to give more desirable therapeutic effect because of irreversible covalent binding to DNA.…”