The interactions of oligonucleotide analogs, 12-mers, which contain deoxyribo- or 2′-O-methylribose sugars and methylphosphonate internucleotide linkages with complementary 12-mer DNA and RNA targets and the effect of chirality of the methylphosphonate linkage on oligomer-target interactions was studied. Oligomers containing a single Rp or Sp methylphosphonate linkage (type 1) or oligomers containing a single phosphodiester linkage at the 5′-end followed by 10 contiguous methylphosphonate linkages of random chirality (type 2) were prepared. The deoxyribo- and 2′-O-methylribo- type 1 12-mers formed stable duplexes with both the RNA and DNA as determined by UV melting experiments. The melting temperatures, Tms, of the 2′-O-methylribo-12-mer/RNA duplexes (49-53°C) were higher than those of the deoxyribo-12mer/ RNA duplexes (31-36°C). The Tms of the duplexes formed by the Rp isomers of these oligomers were approximately 3-5°C higher than those formed by the corresponding Sp isomers. The deoxyribo type 2 12-mer formed a stable duplex, Tm 34°C, with the DNA target and a much less stable duplex with the RNA target, Tm <5°C. In contrast, the 2′-O-methylribo type 2 12-mer formed a stable duplex with the RNA target, Tm 20°C, and a duplex of lower stability with the DNA target, Tm <5°C. These results show that the previously observed greater stability of oligo-2′-Omethylribonucleotide/RNA duplexes versus oligodeoxyribonucleotide/ RNA duplexes extends to oligomers containing methylphosphonate linkages and that the configuration of the methylphosphonate linkage strongly influences the stability of the duplexes.
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