Oligonucleotides and Polynucleotides as Biologically Active Compounds

Conformational evaluation of labeled C3′‐O‐P‐13CH2‐O‐C4″ phosphonate internucleotide linkage, a phosphodiester isostere

“…Study on DNA polymerase selectivity toward 4 0 -methyl-TTP (formation of the Type II DNA oligomer) reported by Marx 19 showed a low influence of the 4 0 -methyl group on the polymerization of the substrate and hybridization of the formed modified DNA as well. In our previous communication, 18 we also confirmed a low influence of the methyl group by measurement of the hybridization capability of phosphodiester 4 0 -methyl-dT 15 (Type II) oligomer in comparison with that of the natural one (Type A). However, the study on hybridization of the phosphonate 4 0 -methyl-dT 15 (Type IV and V) showed 18 a strong decrease in the hybridization capability in case of both IV and V modifications, though to a different extent (interestingly, a similar effect was observed in case of another type of isosteric internucleotide linkage III in which the 5 0 -oxygen atom was replaced by methylene group).…”

“…In our previous communication, 18 we also confirmed a low influence of the methyl group by measurement of the hybridization capability of phosphodiester 4 0 -methyl-dT 15 (Type II) oligomer in comparison with that of the natural one (Type A). However, the study on hybridization of the phosphonate 4 0 -methyl-dT 15 (Type IV and V) showed 18 a strong decrease in the hybridization capability in case of both IV and V modifications, though to a different extent (interestingly, a similar effect was observed in case of another type of isosteric internucleotide linkage III in which the 5 0 -oxygen atom was replaced by methylene group). 20,21 Having excluded any dramatic role of the sugar pucker in influencing the properties of the Type IV (95 % of the C2 0 -endo conformation was found), we reasoned that in all likelihood, it is just the changed conformation of the modified internucleotide linkage due to the 5 0 CH 2 $ 5 0 O transposition which serves as the main factor influencing hybridization properties.…”

“…Second, the use of ab initio calculations along with molecular dynamics (MD) simulations in order to observe the most populated conformations and specify main structural elements governing the conformational preferences. To deal with and aptamer strategies [13][14][15] and those based on artificial ribozymes 16 and siRNAs. 17 Our work also proceeded to the preparation of thymidine oligomers with C3 0 -O-P-CH 2 -O-C4@ linkages which are isosteric with, and closely related to, the classical phosphodiester bond ( Figure 1, scaffold I).…”

Novel isosteric, isopolar phosphonate analogs of oligonucleotides: Preparation and properties

“…To treat the latter condition, numerous chemical modifications have been made to overcome this problem. 3,[6][7][8] Though the phosphorothioate oligonucleotides have long been accepted as a sufficiently stable, useful alternative to natural phosphodiester oligomers, they are not free from unwanted properties (nonspecific binding) and, though antisense oligonucleotides, mostly as chimeric constructs with 2 0 -O-methyl oligoribonucleotides, were able to proceed to clinical testing and use, [8][9][10] the complexity of problems associated with specifying suitable candidates for practical use still warrants further search for an optimum type of enzyme-stable internucleotide linkage.…”

A frequency Domain Phase/Modulation Technique for Intracellular Multicomponent Fluorescence Analysis: Technical Approach and Pharmacological Applications

“…early enough to prevent cellular enzymatic machinery from starting production of pathogens, are under development. In this framework, the use of synthetic oligonucleotides in the regulation of the gene expression by antisense and antigene strategies brings new promising therapeutic opportunities [1][2][3][4][5][6]. The main prerequisites to a successful use of oligonucleotides as plausible antisense candidates involve the ability to penetrate into cells (cell uptake) and to reach their target (distribution), a satisfactory resistance against nucleases (stability), abilities to hybridise with the target sequence and to promote RNase H activity [6,7].…”