MODIFIED OLIGONUCLEOTIDES FOR TELOMERASE INHIBITION
Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior cellular uptake characteristics.
1 . A compound comprising the structure:
O-( x -L) n ,
wherein:
O is an oligonucleotide comprising at least 5 bases complementary to the human telomerase RNA sequence (SEQ ID NO:1);
x is an optional linker;
L is a lipid moiety;
and n is an integer from 1-5, wherein if n>1, each (x-L) component is independently selected.
2 . A compound of claim 1 wherein O comprises at least 10 bases complementary to the human telomerase RNA sequence (SEQ ID NO:1).
3 . A compound of claim 2 wherein L is a lipid selected from the group consisting of substituted and unsubstituted fatty acids and sterols.
4 . A compound of claim 3 wherein L is a fatty acid substituted with fluorine.
5 . A compound of claim 2 wherein L is a substituted or unsubstituted hydrocarbon.
6 . A compound of claim 5 wherein L is a hydrocarbon substituted with fluorine.
7 . A compound of claim 1 wherein n=1 and the x-L component is covalently conjugated to the 5′ terminus of the oligonucleotide O.
8 . A compound of claim 1 wherein n=1 and the (x-L) component is covalently conjugated to the 3′ terminus of the oligonucleotide O.
9 . A compound of claim 1 wherein n=2, one independently selected (x-L) component is covalently conjugated to the 5′ terminus and one independently selected (x-L) component is covalently conjugated to the 3′ terminus.
10 . A compound of claim 1 wherein n=1 and the (x-L) component is covalently conjugated to a nucleobase on the oligonucleotide O.
11 . A compound of claim 1 wherein the internucleoside linkages of the oligonucleotide O are phosphoramidate linkages.
12 . A compound of claim 1 wherein the internucleoside linkages of the oligonucleotide O are N3′→P5′ thiophosphoramidate linkages.
13 . A compound of claim 1 wherein oligonucleotide O comprises at least 10 bases complementary to the human telomerase RNA sequence (SEQ ID NO:1)
14 . A compound of claim 1 wherein:
the internucleoside linkages of the oligonucleotide O are N3′→P5′ thiophosphoramidate linkages;
the sequence of O comprises at least 12 bases complementary to the human telomerase RNA sequence (SEQ 1D NO:1);
n=1;
(x-L) is covalently linked to the 5′ or 3′ terminus of O; and
L is a fatty acid.
15 . A compound of claim 14 wherein x is a glycerol or aminoglycerol linker.
16 . A compound of claim 15 wherein the structure of the compound is:
17 . A compound of claim 14 wherein L is directly linked to the 3′ terminus of the oligonucleotide L through an amide bond.
18 . A compound of claim 17 wherein the structure of the compound is:
19 . A method of inhibiting the activity of a telomerase enzyme, the method comprising contacting the telomerase enzyme with a compound according to claim 1 .
20 . A method of inhibiting the activity of a telomerase enzyme in a cell, the method comprising contacting the cell with a compound according to claim 1 .
21 . The method of claim 20 , wherein the cell is a cancer cell.
22 . A method of inhibiting the proliferation of a cancer cell, the method comprising contacting the cell with a compound according to claim 1 .
23 . A pharmaceutical composition comprising a compound according to claim 1 formulated in a pharmaceutically acceptable excipient.
24 . Use of a compound according to claim 1 in medicine.
25 . Use of a compound according to claim 1 for treating cancer.