Interactions of oligonucleotide analogs containing methylphosphonate internucleotide linkages and 2'-O-methylribonucleosides.
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 degrees C) were higher than those of the deoxyribo-12mer/RNA duplexes (31-36 degrees C). The Tms of the duplexes formed by the Rp isomers of these oligomers were approximately 3-5 degrees C higher than those formed by the corresponding Sp isomers. The deoxyribo type 2 12-mer formed a stable duplex, Tm 34 degrees C, with the DNA target and a much less stable duplex with the RNA target, Tm < 5 degrees C. In contrast, the 2'-O-methylribo type 2 12-mer formed a stable duplex with the RNA target, Tm 20 degrees C, and a duplex of lower stability with the DNA target, Tm < 5 degrees C. These results show that the previously observed greater stability of oligo-2'-O-methylribonucleotide/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.
Kean
J M
JM
Department of Biochemistry, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205.
Cushman
C D
CD
Kang
H
H
Leonard
T E
TE
Miller
P S
PS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D004355:Drug Stability; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012313:RNA / Q000737:chemistry; D013237:Stereoisomerism; D013696:Temperature
D046911:Macromolecular Substances; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; C024341:2'-O-methyladenosine; D006151:Guanosine; C032627:methylphosphonic acid; D012313:RNA; D004247:DNA; D000241:Adenosine; C024900:2'-O-methylguanosine