Enhanced Diagnostic Tools
For practical use in antisense approaches, chemically modified oligonucleotides should possess: (i) high resistance to nuclease degradation and (ii) high affinity to the target RNA strand, along with excellent RNA selectivity.1 Although during the past few decades several chemically modified oligonucleotides with robust ability to bind RNA have been developed, most also have an increased affinity to complementary DNA.2 Conformationally restricted amide-linked nucleic acids3 and 2',5'-linked DNA4 have been reported to have selective binding affinity for complementary RNAs. However, in most cases, their hybridizing ability to complementary RNAs was similar to or less than that observed for natural DNA, which greatly restricts their usefulness for practical applications, such as in antisense technology and for diagnostic purposes. Recently, α-LNA5 and a-L-LNA6 have been reported to have excellent RNA specific binding affinity via parallel motif hybridization. Nevertheless, it was concluded that the thermal stability of parallel duplexes is lower than those of corresponding antiparallel duplexes. Backbone extended pyrrolidine peptide nucleic acids (bep-PNA)7 and thioacetamido nucleic acids (TANA)8 also possessed promising RNA selective binding affinity. However, their mode of RNA targeting was achieved via triplex formation, which requires the use of two folds of antisense nucleic acids. In addition to that, PNA has its own problems that restrict its usefulness, including limited aqueous solubility, poor cellular uptake9 and ambiguity in binding complementary DNA/RNA in both parallel and antiparallel orientations.10 Our aim is to develop an antisense oligonucleotide that is sufficiently stable in physiological conditions and binds well to RNA complements while at the same time, showing lower affinity to DNA complements. Oligonucleotides which meet these criteria are likely to be much more useful for in vivo antisense applications
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