Oligonucleotide N3′→P5′ thiophosphoramidates: their synthesis and administration to treat neoplasms
AssigneeGeron Corporation
InventorsSergei Gryaznov, Krisztina Pongracz, Tracy Matray
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Abstract
Oligonucleotides with a novel sugar-phosphate backbone containing at least one internucleoside 3′-NHP(O)(S−)O-5′ linkage, and methods of synthesizing and using the inventive oligonucleotides are provided. The inventive thiophosphoramidate oligonucleotides were found to retain the high RNA binding affinity of the parent oligonucleotide N3′→P5′ phosphoramidates and to exhibit a much higher acid stability.
Claims19
An oligonucleotide comprising a sequence of nucleoside subunits joined by N3′→P5′ thiophosphoramidate inter-subunit linkages, wherein the oligonucleotide comprises a sequence selected from the group consisting of:
- GTTAGGGTTAG (SEQ ID NO:1);
- TAGGGTTAGACAA (SEQ ID NO:2);
- and
- CAGTTAGGGTTAG (SEQ ID NO:8)
- and wherein the N3′→P5′ thiophosphoramidate inter-subunit linkages have the structure 3′-[—NH—P(═O)(—SR)—O—]-5′, wherein R is selected from the group consisting of hydrogen, alkyl, and aryl;
- and pharmaceutically acceptable salts thereof.
A method of formulating a pharmaceutical composition, comprising combining an oligonucleotide according to claim with a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.