Targeted nucleic acid conjugate compositions
The invention provides conjugates that comprise a targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic nucleic acids to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
1. The compound:
or a salt thereof, wherein Q is -L 1 -R 1 ;
L 1 is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 14 carbon atoms, wherein one or more of the carbon atoms in the hydrocarbon chain is optionally replaced with —NR X —C(═O)—, or —C(═O)—NR X —, and wherein R X is hydrogen or (C 1 -C 6 )alkyl, and wherein the hydrocarbon chain, is optionally substituted with oxo(═O); or
L 1 is selected from the group consisting of:
R 1 has the following formula:
wherein:
B 1 is CH;
B 2 is selected from the group consisting of:
B 3 is selected from the group consisting of:
T 1 is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more of the carbon atoms in the hydrocarbon chain is optionally replaced by —NR X —C(═O)—, or —C(═O)—NR X —, and wherein R X is hydrogen or (C 1 -C 6 )alkyl, and wherein the hydrocarbon chain, is optionally substituted with oxo (═O), that is covalently bonded to B 1 ;
T 2 is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more of the carbon atoms in the hydrocarbon chain is optionally replaced by —NR X —C(═O)—, or —C(═O)—NR X —, and wherein R X is hydrogen or (C 1 -C 6 )alkyl, and wherein the hydrocarbon chain, is optionally substituted with oxo (═O), that is covalently bonded to B 1 ;
each of T 3 , T 4 , T 5 , and T 6 is independently selected from the group consisting of:
n=1, 2, or 3;
each saccharide is independently selected from the group consisting of:
R 2 is a siRNA substituent; and
R′ is C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl; wherein the C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl are optionally substituted with halo or hydroxyl.
2. The compound or salt of claim 1 , wherein L 1 is connected to R 1 through —NH—, —O—, —S—, —(C═O)—, —(C═O)—NH—, —NH—(C═O)—, —(C═O)—O—, —NH—(C═O)—NH—, or —NH—(SO 2 )—.
3. The compound of claim 1 , wherein each saccharide is independently:
4. A pharmaceutical composition comprising a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A method to deliver siRNA to the liver of an animal in need thereof comprising administering a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the animal in need thereof.
6. The compound of claim 1 , wherein n=1.
7. The compound of claim 1 , wherein n=2.
8. The compound of claim 1 , wherein n=3.
9. The compound of claim 1 , wherein B 2 is selected from the group consisting of:
10. The compound of claim 1 , wherein B 3 is selected from the group consisting of:
11. The compound of claim 1 , wherein L 1 is selected from the group consisting of: