Lipids for lipid nanoparticle delivery of active agents
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , G 1 , G 2 , and G 3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
1. A method for inducing expression of a protein in a mammal, comprising administering to the mammal a lipid nanoparticle comprising:
i) a compound having the following structure (I):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 is optionally substituted C 1 -C 24 alkyl or optionally substituted C 2 -C 24 alkenyl;
R 2 and R 3 are each independently optionally substituted C 1 -C 36 alkyl;
R 4 and R 5 are each independently optionally substituted C 1 -C 6 alkyl, or R 4 and R 5 join, along with the nitrogen atom to which they are attached, to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
L 1 , L 2 , and L 3 are each independently optionally substituted C 1 -C 18 alkylene;
G 1 is a direct bond, —(CH 2 ) n O(C═O)—, —(CH 2 ) n (C═O)O—, or —(C═O)—;
G 2 and G 3 are each independently —(C═O)O— or —O(C═O)—; and
n is an integer greater than 0; and
ii) an mRNA encoding the protein.
2. The method of claim 1 , wherein expression of the protein induces a pharmacological effect in the mammal.
3. The method of claim 2 , wherein the pharmacological effect is increased production of red blood cells.
4. The method of claim 2 , wherein the pharmacological effect is protection against infection.
5. The method of claim 1 , wherein the mRNA encodes a protein of an infectious agent.
6. The method of claim 5 , wherein the infectious agent is a virus.
7. The method of claim 1 , wherein the mRNA encodes an antibody.
8. The method of claim 1 , wherein the mammal is a non-human primate.
9. The method of claim 1 , wherein the mammal is a human.
10. The method of claim 1 , wherein the compound has the following structure (IA):
11. The method of claim 1 , wherein the compound has the following structure (IB):
12. The method of claim 1 , wherein R 1 is optionally substituted C 6 -C 18 alkyl or optionally substituted C 14 -C 18 alkenyl.
13. The method of claim 1 , wherein G 1 is a direct bond.
14. The method of claim 1 , wherein G 1 is —(CH 2 ) n (C═O)O— and n is greater than 1.
15. The method of claim 1 , wherein L 1 is unsubstituted C 1 -C 6 alkylene.
16. The method of claim 1 , wherein R 2 and R 3 are both unsubstituted C 8 -C 24 alkyl.
17. The method of claim 1 , wherein R 2 and R 3 each independently have one of the following structures:
wherein:
R 6 and R 7 are each independently unsubstituted C 2 -C 12 alkyl.
18. The method of claim 1 , wherein R 2 and R 3 each independently have one of the following structures:
19. The method of claim 1 , wherein L 2 and L 3 are each independently unsubstituted C 4 -C 10 alkylene.
20. The method of claim 1 , wherein R 4 and R 5 are both methyl, ethyl or n-butyl.
21. The method of claim 1 , wherein R 4 and R 5 join, along with the nitrogen atom to which they are attached, to form a heterocyclyl ring having the following structure:
22. The method of claim 1 , wherein the compound has one of the following structures: