초록 ▼

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 af

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.

대표청구항 ▼

What is claimed is: 1. A method of inhibiting human telomerase enzyme activity in a subject in need thereof, comprising contacting the enzyme with an oligonucleotide comprising nucleoside subunits joined by inter-subunit linkages, wherein the oligonucleotide comprises a contiguous sequence of at le

What is claimed is: 1. A method of inhibiting human telomerase enzyme activity in a subject in need thereof, comprising contacting the enzyme with an oligonucleotide comprising nucleoside subunits joined by inter-subunit linkages, wherein the oligonucleotide comprises a contiguous sequence of at least 10 nucleoside subunits complementary to the RNA component of human telomerase, and wherein said at least 10 subunits are joined by N3'→N5' thiophosphoramidate linkages having 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. 2. A method of inhibiting proliferation of a cell that expresses human telomerase in vitro comprising contacting the cell with an oligonucleotide comprising nucleoside subunits joined by inter-subunit linkages, wherein the oligonucleotide comprises a contiguous sequence of at least 10 nucleoside subunits complementary to the RNA component of human telomerase, and wherein said at least 10 nucleoside subunits are joined by N3'→P5' thiophosphoramidate linkages having 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. 3. A method of inhibiting proliferation of a cancer cell that expresses human telomerase in a subject in need thereof comprising contacting the cell with an oligonucleotide comprising nucleoside subunits joined by inter-subunit linkages, wherein the oligonucleotide comprises a contiguous sequence of at least 10 nucleoside subunits complementary to the RNA component of human telomerase, and wherein said at least 10 nucleoside subunits are joined by N3n'→P5' thiophosphoramidate linkage having the structure 3'-[--NH--P(═O)(SR)--O--]-5', wherein R is selected from the group consisting of hydrogen, alkyl, and pharmaceutically acceptable salt thereof. 4. The method of claim 3 wherein the cell is a cell. 5. A method of inhibiting human telomerase enzyme activity in vitro, comprising contacting the enzyme with an oligonucleotide comprising nucleoside subunits joined by inter-subunit linkages, wherein the oligonucleotide comprises a contiguous sequence of at least 10 nucleoside subunits complementary to the RNA component of human telomerase, and wherein said at least 10 subunits are joined by N3'-> N5'thiophosphoramidate linkages having 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.