Synthetic glucopyranosyl lipid adjuvants
Compounds, particularly, glucopyranosyl lipid adjuvant (GLA) compounds, having the following structure (I) are provided: or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , are as defined herein. Pharmaceutical compositions, vaccine compositions, and related methods for inducing or enhancing immune responses, are also provided.
1. A GLA compound having the following structure (IV):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 , L 2 , L 3 , and L 4 are the same or different and independently —O—, —NH— or —(CH 2 )—;
Y 1 is an acid functional group;
Y 2 and Y 3 are the same or different and independently —OH, —SH, or an acid functional group; and
Y 4 is —OH or —SH.
2. A GLA compound according to claim 1 , wherein Y 1 is —OP(═O)(OH) 2 and Y 2 , Y 3 and Y 4 are each —OH.
3. A GLA compound according to claim 1 , wherein L 1 and L 3 are both —O— and L 2 and L 4 are both —NH.
4. A GLA compound according to claim 1 , wherein Y 1 is —OP(O)(OH) 2 , Y 2 , Y 3 and Y 4 are each —OH, L 1 and L 3 are both —O—, and L 2 and L 4 are both —NH.
5. A GLA compound having the following structure (IX):
or a pharmaceutically acceptable salt thereof.
6. A vaccine composition comprising a compound in combination with an antigen or a recombinant expression vector encoding an antigen, wherein the compound has the following structure (IV):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 , L 2 , L 3 , and L 4 are the same or different and independently —O—, —NH— or —(CH 2 )—;
Y 1 is an acid functional group;
Y 2 and Y 3 are the same or different and independently —OH, —SH, or an acid functional group; and
Y 4 is —OH or —SH.
7. The vaccine composition of claim 6 wherein the recombinant expression construct is viral vector.
8. The vaccine composition of claim 7 wherein the viral vector is selected from the group consisting of an adenovirus vector, an adeno-associated virus vector, a herpesvirus vector, a lentivirus vector, a poxvirus vector and a retrovirus vector.
9. A method of eliciting or enhancing an antigen-specific immune response in a subject, the method comprising administering to the subject a vaccine composition of claim 6 .
10. A pharmaceutical composition comprising a compound and pharmaceutically acceptable carrier or excipient, wherein the compound has the following structure (IV):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 , L 2 , L 3 , and L 4 are the same or different and independently —O—, —NH— or —(CH 2 )—;
Y 1 is an acid functional group;
Y 2 and Y 3 are the same or different and independently —OH, —SH, or an acid functional group; and
Y 4 is —OH or —SH.
11. A method for stimulating a non-specific immune response in a subject comprising administering to the subject a pharmaceutical composition of claim 10 .
12. The vaccine composition of claim 6 , wherein Y 1 is —OP(═O)(OH) 2 and Y 2 , Y 3 and Y 4 are each —OH.
13. The vaccine composition of claim 6 , wherein L 1 and L 3 are both —O— and L 2 and L 4 are both —NH—.
14. The vaccine composition of claim 6 , wherein the compound has the following structure (IX):
or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of claim 10 , wherein Y 1 is —OP(═O)(OH) 2 and Y 2 , Y 3 and Y 4 are each —OH.
16. The pharmaceutical composition of claim 10 , wherein L 1 and L 3 are both —O— and L 2 and L 4 are both —NH—.
17. The pharmaceutical composition of claim 10 , wherein the compound has the following structure (IX):
or a pharmaceutically acceptable salt thereof.
18. The vaccine composition of claim 6 wherein the antigen comprises a polypeptide antigen.
19. The method of claim 9 , wherein the compound in the vaccine composition is a compound having the following structure (IX):
or a pharmaceutically acceptable salt thereof.
20. The method of claim 11 , wherein the compound in the pharmaceutical composition is a compound having the following structure (IX):
or a pharmaceutically acceptable salt thereof.