Bridged nucleic acid
Bridged nucleic acids (BNAs) are modified RNA nucleotides. They are sometimes also referred to as constrained or inaccessible RNA molecules. BNA monomers can contain a five-membered, six-membered or even a seven-membered bridged structure with a “fixed” C3’-endo sugar puckering. The bridge is synthetically incorporated at the 2’, 4’-position of the ribose to afford a 2’, 4’-BNA monomer. The monomers can be incorporated into oligonucleotide polymeric structures using standard phosphoamidite chemistry. BNAs are structurally rigid oligo-nucleotides with increased binding affinities and stability.
Chemical structures of BNA monomers containing a bridge at the 2’, 4’-position of the ribose to afford a 2’, 4’-BNA monomer as synthesized by Takeshi Imanishi’s group. The nature of the bridge can vary for different types of monomers. The 3D structures for A-RNA and B-DNA were used as a template for the design of the BNA monomers. The goal for the design was to find derivatives that possess high binding affinities with complementary RNA and/or DNA strands.
The presence of 2’-hydroxyls in the RNA backbone favors a structure that resembles the A-form structure of DNA. The flexible five-membered furanose ring in nucleotides exists in equilibrium of two preferred conformations of the N- (C3’-endo, A-form) and the S-type (C2’-endo, B-form) as illustrated in the next figure.
An increased conformational inflexibility of the sugar moiety in nucleosides (oligonucleotides) results in a gain of high binding affinity with complementary single-stranded RNA and/or double-stranded DNA. The first 2’,4’-BNA (LNA) monomers were first synthesized by Takeshi Imanishi’s group in 1997 followed independently by Jesper Wengel’s group in 1998.
Chemical structures of other BNAs that were synthesized in the past years as indicated below the structures.
BNA nucleotides can be incorporated into DNA or RNA oligonucleotides at any desired position. Such oligomers are synthesized chemically and are now commercially available. The bridged ribose conformation enhances base stacking and pre-organizes the backbone of the oligonucleotide significantly increasing their hybridization properties.
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