Oligonucleotide N3′→N5′Phosphoramidate...

Details Oligonucleotide N3′→N5′Phosphoramidate... Oligonucleotide N3′→N5′Phosphoramidate...

1997-09-03

2001-01-02

Priebe, Scott D. (Department: 1632)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S006120

Utility Patent

active

06169170

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to hybridization and nuclease resistance methods employing oligonucleotide N3′→P5′ phosphoramidates.
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BACKGROUND OF THE INVENTION
Oligonucleotides have been proposed as potent diagnostic compounds and as new rationally designed therapeutic agents (Uhlman, 1990; Helene, et al., 1990; Helene, 1991). The mechanism of action of these compounds is based on their specific interaction with RNA or DNA regions of interest.
Several modifications of the natural phosphodiester internucleoside bond {phosphomono- (Eckstein, et al., 1985; Cohen, 1993) or dithioate (Marshall, et al., 1993), methylphosphonate (Miller, 1991), phosphodiester amidate (Letsinger, et al., 1988; Froehler, et al., 1988)} have been introduced to improve (i) the stability of the oligomers in biological media, and (ii) the hybridization properties of the oligomers.
Unfortunately, the vast majority of these analogs exhibit reduced binding with target RNA or DNA strands via duplex or triplex formation (Kibler-Herzog, et al., 1991). Moreover, the presence of the stereoisomers at phosphorous in some of these analogs may complicate the binding patterns with complimentary nucleic acids (LaPlauche, et al., 1986; Bower, et al., 1987; Tidd, et al., 1988).
SUMMARY OF THE INVENTION
Methods and compositions of the present invention relate to oligodeoxyribonucleotides having contiguous nucleoside subunits joined by intersubunit linkages. In the oligonucleotides, at least 2 contiguous subunits are joined by N3′→P5′ phosphoramidate intersubunit, or greater than 3 of the total intersubunit linkages are N3′→P5′ phosphoramidate intersubunit linkages.
An exemplary N3′→P5′ phosphoramidate intersubunit linkage is shown in
FIG. 2A
, where X is —O
−
, —OR or —R, and R is selected from the group consisting of alkyl, alkenyl, aryl, and alkaryl. For definitions of these exemplary substituent groups see the Definitions section below.
The nucleosi

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