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Development of artificial nucleic acids is essential to design diagnostic probes or potentially new drugs for oligonucleotide-based therapies. Of particular interest are artificial nucleic acids with the following characteristics:
As a pioneer in oligonucleotide synthesis, Bio-Synthesis Inc. has been pursuing the development of new oligonucleotide-based techniques that can produce compounds with superior binding affinity and chemical/biological stability. As such, Bio-Synthesis Inc. has introduced a third generation of nucleic acid analogs, Bridged Nucleic Acid (BNA). BNA is based on multi-functional synthetic RNA analogues that can be used in place of the first generation bridged nucleic acids known as Locked Nucleic Acids (LNA). BNA can be spiked with DNA or RNA in order to modify the structural formation of the nucleic acid helices. Also, when compared to Peptide Nucleic Acids (PNA), BNA allows for better base-pair stacking and a high stability, making BNA based oligonucleotides an ideal solution for the detection of small or highly similar DNA/RNA targets.
Bio-Synthesis Inc. is now providing synthetic oligonucleotides containing BNA which are deprotected, desalted or HPLC purified. All oligonucleotides are quality checked by MALDI-TOF Mass Spectrometry.
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BNA oligonucleotides exhibit significantly higher affinity to their complementary strands when compared to previous generations of constrained nucleic acids (PNA & LNA). Their extraordinary level of sensitivity and specificity for nuclease-resistant activity makes BNA a superior tool for developing high value detection systems and therapeutic products.
Bio-Synthesis, home of BNATM oligonucleotides
Bio-Synthesis is licensed by BNA Inc as an exclusive provider of synthetic BNA. Purchase of BNA for research use carries a "research use-only license". Clinical, therapeutic or commercial applications of BNA require a separate "commercial license".
Natural nucleic acids have a higher degree of freedom in their chemical structure. This feature is thermodynamically unfavorable for DNA-DNA and RNA-RNA double strand formation (hybridization) and is often subject to degradation by both endo and exonucleases. Improving binding affinity (hybridizing capability) is yet unresolved for highly sensitive gene-targeting applications.
Bridged nucleic acid 2',4'-BNANC (2'-O,4'-aminoethylene bridged nucleic acid) is a compound containing a six-member bridged structure with an N-O linkage. This novel nucleic acid analogue can be synthesized and incorporated into oligonucleotides. When compared to the earlier generation of LNA, BNA was found to possess:
Based on the above results, BNA has shown great promise for applications in antisense and antigene technologies.
BNA can be easily incorporated into oligonucleotide strands. This feature allows for designing BNA hybrid oligos to satisfy the need for very high and sequence-specific hybridization with nucleic acids. Additionally, BNA possesses a strong nuclease-resistant property. Due to these outstanding properties, Bio-Synthesis Inc. now offers the third generation BNA (BNANC).
BNA oligos allow greater flexibility in the design of primers and probes. They can be mixed with DNA, RNA and other nucleic acid analogs using standard phosphoramidite synthesis chemistry. BNA oligonucleotides are also easily labeled or modified with standard oligonucleotide tags such as DIG, fluorescent dyes, biotin, amino-linkers, etc.
BNA monomers can be mixed within DNA, RNA, and other oligonucleotides to facilitate changes in Tm (melting temperature) without losing specificity. This feature can be used to optimize the Tm of oligonucleotides, and can shorten probe design while maintaining Tm. These are beneficial in microRNA research, PCR, microarray, and other applications where hybridization sensitivity and specificity are necessary.
Unlike its predecessor LNA, BNA possesses stronger resistance to nuclease and possesses better flexibility, both of which allow for effective duplex and triplex formation. This gives BNA oligonucleotides a high binding affinity to ssRNA and dsDNA, and makes BNA oligos an excellent tool for in-vivo applications.
Older generations of 2',4'-LNA do not posses sufficient resistant to nuclease, nor the flexibility required for efficient triplex formation. The increased duplex and triplex-forming ability of BNA conforms with the Watson-Crick binding and gives nBNATM oligonucleotides a high binding affinity to ssRNA and dsDNA. This strand invading property makes BNATM an excellent tool for in vivo applications. Incorporating BNA into oligonucleotides, further enhanced resistance against nuclease degradation and leads to high in vitro and in vivo stability, making BNANC a promising therapeutic agent.
The physiological properties of BNA such as water solubility are very similar to those of DNA and RNA. BNA can therefore be easily adapted to conventional experimental protocols, incorporated into DNA/RNA oligonucleotide synthesis, and utilized in biochemical analysis methods.
Although siRNA stimulates RNAi activity in cells, its in-vivo usage as a drug remains questionable because of low biostability and undesirable toxicity (off-target effects). To overcome these problems, nucleotide analogue usage is increasing daily.
One example is the use of Locked Nucleic Acids (LNA), the 1st generation Bridged Nucleic Acids. These have been reported to have good RNA specific binding affinity. However, LNA’s resistance to nuclease activity is significantly lower than that of phosphorothioate-containing (PS) oligonucleotides. Also, oligonucleotides containing consecutive LNA bases are very rigid, resulting in inefficient triplex formation.
Another example is Peptide nucleic acids (PNA) which also possesses promising RNA selective binding affinity. However, their mode of RNA targeting is achieved via triplex formation, which requires the use of two folds of antisense nucleic acids. In addition to that, PNA has limited aqueous solubility, poor cellular uptake, and ambiguity in binding complementary DNA/RNA in both parallel and antiparallel orientations.
Current research has shown that the nucleotide analogues 2', 4'-BNA, unlike LNA and PNA, are substantially compatible with in-vivo siRNA or antisense technology.