Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-01-17
1998-06-23
Marschel, Ardin H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
435 6, 536 231, 536 253, 536 2533, C12Q 168, C07H 1900, C07H 2102, C07H 2104
Patent
active
057707138
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to phosphorothioate triester oligonucleotide compounds and to a method of preparation.
In the present application, the term "oligonucleotides" generally speaking indicates a DNA or RNA polynucleotide, that is to say one in the ribo- (RNA) or deoxyribo- (DNA), or even mixed ribo-deoxyribo, series. These oligonucleotides are in general formed by a linkage of 2 to 100 nucleotides, and more generally, of 5 to 50 nucleotides.
These oligonucleotides are used for biological or therapeutic purposes according to different approaches: antisense (formation of duplex), anti-gene (formation of triple helixes), catalytic (RNA with ribozyme activity) or sense (protein target).
The antisense oligonucleotides are short synthetic DNA or RNA or mixed molecules of complementary sequences to a target sequence belonging to a gene or to an RNA messenger whose expression it is specifically desired to block. The antisense oligonucleotides are in fact directed against a messenger RNA sequence, or alternatively against a DNA sequence and hybridize to the sequence to which they are complementary, thus being able to block genetic expression.
The antisense deoxyribonucleotides can also be directed against certain bicatenary DNA regions (homopurine/ homopyrimidine sequences or sequences rich in purines/pyrimidines) and thus form triple helixes. These oligonucleotides directed in this way against DNA have been called "anti-gene" or alternatively "anti-code". The formation of a triple helix, at a particular sequence, can block the fixing of proteins intervening in the expression of a gene and/or allow irreversible damage to be introduced into the DNA if the oligonucleotide under consideration possesses a particular reactive group. Such antisense oligonucleotides can form artificial restriction endonucleases, directed against specific sequences.
In cells, and more particularly in an organism, in the blood circulation, for example, the natural oligonucleotides are sensitive to degradation by nucleases. Nucleases are degradation enzymes capable of cutting the phosphodiester bonds of DNA or of RNA, either by introducing internal cleavages into mono- or bicatenary molecules, or by attacking these molecules starting from their ends. The enzymes which attack internally are called endonucleases and those attacking by the ends are called exonucleases.
The use of oligonucleotides encounters two major problems which are, on the one hand, great sensitivity to degradation by exonucleases which are found as well in the serum or in extracellular medium or in intracellular cytoplasmic medium and, on the other hand, low intra-cellular penetration.
The use of modified oligonucleotides has already been proposed to increase the stability of oligonucleotides or favor penetration through cellular membranes or alternatively to stabilize hybridization and specific affinity for a target sequence, whether this be a single or double strand nucleic acid, or even a protein, or alternatively to increase the interaction with said target sequence. Chemical modifications of the structural skeleton of the molecule or derivations or couplings to reactive or intercalating groups have been proposed, in general localized at the end of the oligonucleotides.
As far as the chemical modifications of the skeleton are concerned, it has been proposed to modify the nature of the internucleotide phosphate linkage, especially in the form of methylphosphonate, phosphorothioate or phosphorodithioate; or alternatively by modifying the sugar part, especially by an alpha-anomeric configuration, a 2'--O--CH.sub.3 substitution or by replacing the oxygen of the furan ring by a sulfur (4'-thioribonucleotide). It has also been proposed to modify the nucleotide bases.
Thus, in French Patent Applications FR 83 01223 (2 540 122) and FR 84 11795 (2 568 254) chemical compounds formed by an oligonucleotide including natural or modified linkage of .beta.-nucleotides have been described, on which are found, fixed by a covalent bond, at least one intercalating group, which c
REFERENCES:
patent: 5210264 (1993-05-01), Yau
Marshall et al. "Phosphorodithioate DNA as a Potential Therapeutic Drug" Science, vol. 259, pp. 1564-1570, Mar. 1993.
Imbach Jean-Louis
Rayner Bernard
Centre National de la Recherche Scientifique
Marschel Ardin H.
Riley Jezia
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