TLR agonists
The present invention provides for TLR agonist conjugates (compounds) and compositions, as well as methods of using them. The compounds of the invention are broad-spectrum, long-lasting, and non-toxic combination of synthetic immunostimulatory agents, which are useful for activating the immune system of a mammal, preferably a human and can help direct the pharmacophore to the receptor within the endosomes of target cells and enhance the signal transduction induced by the pharmacophore.
1. A compound having formula (IA) and R 3 :
wherein X 1 is —O;
R 1 is (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl, wherein the substituents are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, or C 1-6 alkoxy;
wherein n=4 and each R 2 is —H;
X 2 is a bond or a linking group having up to about 24 atoms; wherein the atoms in the chain of the linking group are selected from the group consisting of carbon, nitrogen, sulfur, non-peroxide oxygen, and phosphorous; and R 3 is a protein that directs formula (IA) to receptors within endosomes of target cells;
or a pharmaceutically acceptable salt of the compound,
wherein the ratio of the compound having formula (IA) to R 3 is 5:1.
2. The compound of claim 1 , wherein R 1 is C 1-4 alkyl, or substituted C 1-4 alkyl.
3. The compound of claim 2 , wherein R 1 is CH 3 —, CH 3 —C 2 —, CH 3 CH 2 CH 2 —, hydroxyC 1-4 alkylene, or C 1-4 alkoxyC 1-4 alkylene.
4. The compound of claim 3 , wherein R 1 is CH 3 —, CH 3 —CH 2 —, CH 3 —O—CH 2 CH 2 — or CH 3 —CH 2 —O—CH 2 CH 2 —.
5. The compound of claim 1 , wherein X 2 is a bond or a chain having from about 4 to about 12 atoms.
6. The compound of claim 1 , wherein X 2 is a bond or a chain having from about 6 to about 9 atoms.
7. The compound of claim 1 , wherein X 2 is
8. The compound of claim 1 , wherein the protein is albumin.
9. The compound of claim 1 , wherein the protein is ovalbumin.
10. A compound having formula (IA) and R 3 :
wherein X 1 is —O—;
R 1 is (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl, wherein the substituents are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, or C 1-6 alkoxy;
each R 2 is —H and n=4;
X 2 is a bond or a linking group having up to about 24 atoms; wherein the atoms in the chain of the linking group are selected from the group consisting of carbon, nitrogen, sulfur, and non-peroxide oxygen; and R 3 is a protein that directs formula (IA) to receptors within endosomes of target cells;
or a pharmaceutically acceptable salt of the compound,
wherein the ratio of the compound having formula (IA) to R 3 is 5:1.
11. A pharmaceutical composition comprising the compound of claim 10 , and a pharmaceutically acceptable carrier.
12. The compound of claim 10 , wherein the protein is albumin.
13. The compound of claim 10 , wherein the protein is ovalbumin.