BIFUNCTIONAL CROSSLINKING OLIGONUCLEOTIDES ADAPTED FOR LINKING TO A DESIRED GENE SEQUENCE OF INVADING ORGANISM OR CELL

摘要

Chemically modified oligonucleotides (ODNs) are complementary, either in the sense of the classic "four letter code" recognition motif, or in the sense required for triple strand formation based on the more limited "two letter code recognition motif", to a target sequence of double stranded DNA of an invading cell, organism or pathogen, such as a virus, fungus, parasite, bacterium or malignant cell. The ODNs have cross-linking agents covalently attached at least to two different sites of the ODN. Alternatively, the cross-linking agent which is attached to one site on the ODN has two cross-linking functionalities, and therefore in effect comprises two cross-linking agents. The cross-linking agent typically includes a linker arm (such as an alkyl, alkoxy, aminoalkyl or amidoalkyl chain) and a reactive group which, after triple strand formation with the target sequence of DNA, is capable of reacting with the target DNA to form a covalent bond therewith. Each cross-linking agent of the novel modified therapeutic ODNs is capable of forming a covalent bond with the target DNA. As a result of the covalent bond formation between the modified therapeutic ODN and both strands of the target DNA sequence, replication and expression of the target DNA sequence is inhibited.