Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages

Abstract

Novel chiral compounds that mimic and / or modulate the activity of wild-type nucleic acids are disclosed. In general, the compounds are phosphorothioate oligonucleotides wherein the 5′, and the 3′-terminal internucleoside linkages are chirally Sp and internal internucleoside linkages are chirally Rp.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This patent application is a continuation-in-part of application Ser. No. 09 / 115,027, filed Jul. 14, 1998, now U.S. Pat. No. 6,242,589 entitled “Phosphorothioate Oligonucleotides Having Modified Internucleotide Linkages”, the content of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to the design and synthesis of nuclease resistant phosphorothioate oligonucleotides which are useful for therapeutics, diagnostics and as research reagents. Phosphorothioate oligonucleotides are provided in which all of the internucleoside linkages are chiral. Such compounds are resistant to nuclease degradation and are capable of modulating the activity of DNA and RNA.BACKGROUND OF THE INVENTION[0003]It is well known that most of the bodily states in multi-cellular organisms, including most disease states, are effected by proteins. Such proteins, either acting directly or through their enzymatic or...

AI Technical Summary

Benefits of technology

[0030]In accordance with this theory, the structures 3, 8, 14, 18, 20, and 25 all have geminal disubstituents. Use of this

Problems solved by technology

It is therefore a general object of such therapeutic approaches to interfere with or other-wise modulate gene expression, which would lead to undesired protein formation.

It is unlikely that unmodified, naturally-occurring oligonucleotides will be useful therapeutic agents because they are rapidly degraded by nucleases.

Presently, there is no method to prepare P-chiral oligonucleotides in large scale.

This method suffers from the non-stereospecific synthesis of the synthon.

However, there was reported difficulty in removing the chiral auxiliary protecting group at phosphorous.

This method has yet to be tested for convenient large scale automated synthesis.

However, because of some disadvantageous properties of svPDE, a search for other [Rp]-specific endonucleases was undertaken.

Attempts to improve these yields by increasing either the coupling time or DBU concentration were unsuccessful.

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