Triazole macrocycle systems
The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production. Macrocycles of the invention include triazole moieties that crosslink amino acid side chains. The cross links can stabilize a secondary structure of a peptidomimetic macrocycle, such as an α-helix.
1. A peptidomimetic macrocycle of Formula (I):
wherein:
each A, C, D, and E is independently a natural or non-natural amino acid;
each B is independently a natural or non-natural amino acid, amino acid analog,
[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being optionally substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 ;
L is a macrocycle-forming linker of the formula
each L 1 , L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, C(═O)—O—, or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000;
w is an integer from 1-1000;
and
n is an integer from 1-5,
wherein x+y+z is 2.
2. The peptidomimetic macrocycle of claim 1 , wherein L 1 or L 2 is heteroalkylene.
3. The peptidomimetic macrocycle of claim 1 , wherein L 1 or L 2 is alkylene.
4. The peptidomimetic macrocycle of claim 1 , wherein one of A, B, or C is a non-natural amino acid.
5. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, optionally substituted with halo-.
6. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is methyl.
7. The peptidomimetic macrocycle of claim 1 , wherein at least one of D and E is attached to an additional macrocycle-forming linker.
8. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the peptidomimetic macrocycle is more stable than a corresponding α-helical secondary structure of a corresponding non-macrocyclic polypeptide.
9. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the macrocycle-forming linker spans from 1 turn to 5 turns of the peptidomimetic macrocycle.
10. The peptidomimetic macrocycle of claim 1 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.
11. The peptidomimetic macrocycle of claim 1 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.
12. The peptidomimetic macrocycle of claim 1 , wherein the macrocycle comprises a ring of about 18 atoms to 26 atoms.
13. A peptidomimetic macrocycle of Formula (I):
wherein:
each A, C, D, and E is independently a natural or non-natural amino acid:
each B is independently a natural or non-natural amino acid, amino acid analog,
[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being optionally substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 ;
L is a macrocycle-forming linker of the formula
each L 1 , L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, C(═O)—O—, or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000;
w is an integer from 1-1000;
x is an integer from 0-10;
y is an integer from 0-10;
z is an integer from 0-10; and
n is an integer from 1-5,
wherein at least one of L 1 or L 2 is heteroalkylene.
14. The peptidomimetic macrocycle of claim 13 , wherein one of L 1 or L 2 is alkylene.
15. The peptidomimetic macrocycle of claim 13 , wherein one of A, B, or C is a non-natural amino acid.
16. The peptidomimetic macrocycle of claim 13 , wherein R 1 and R 2 are independently alkyl, optionally substituted with halo-.
17. The peptidomimetic macrocycle of claim 13 , wherein at least one of R 1 and R 2 is methyl.
18. The peptidomimetic macrocycle of claim 13 , wherein at least one of D and E is attached to an additional macrocycle-forming linker.
19. The peptidomimetic macrocycle of claim 13 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the peptidomimetic macrocycle is more stable than a corresponding α-helical secondary structure of a corresponding non-macrocyclic polypeptide.
20. The peptidomimetic macrocycle of claim 13 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the macrocycle-forming linker spans from 1 turn to 5 turns of the peptidomimetic macrocycle.
21. The peptidomimetic macrocycle of claim 13 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.
22. The peptidomimetic macrocycle of claim 13 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.
23. The peptidomimetic macrocycle of claim 13 , wherein the macrocycle comprises a ring of about 18 atoms to 26 atoms.
24. A peptidomimetic macrocycle of Formula (I):
wherein:
each A, C, D, and E is independently a natural or non-natural amino acid;
each B is independently a natural or non-natural amino acid, amino acid analog,
[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being optionally substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 ;
L is a macrocycle-forming linker of the formula
each L 1 , L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, C(═O)—O—, or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000;
w is an integer from 1-1000;
x is an integer from 0-10;
y is an integer from 0-10;
z is an integer from 0-10; and
n is an integer from 1-5,
wherein at least one of D and E is attached to an additional macrocycle-forming linker.
25. The peptidomimetic macrocycle of claim 24 , wherein L 1 or L 2 is alkylene.
26. The peptidomimetic macrocycle of claim 24 , wherein one of A, B, or C is a non-natural amino acid.
27. The peptidomimetic macrocycle of claim 24 , wherein R 1 and R 2 are independently alkyl, optionally substituted with halo-.
28. The peptidomimetic macrocycle of claim 24 , wherein at least one of R 1 and R 2 is methyl.
29. The peptidomimetic macrocycle of claim 24 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the peptidomimetic macrocycle is more stable than a corresponding α-helical secondary structure of a corresponding non-macrocyclic polypeptide.
30. The peptidomimetic macrocycle of claim 24 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the macrocycle-forming linker spans from 1 turn to 5 turns of the peptidomimetic macrocycle.
31. The peptidomimetic macrocycle of claim 24 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.
32. The peptidomimetic macrocycle of claim 24 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.
33. The peptidomimetic macrocycle of claim 24 , wherein the macrocycle comprises a ring of about 18 atoms to 26 atoms.
34. A peptidomimetic macrocycle of Formula (I):
wherein:
each A, C, D, and E is independently a natural or non-natural amino acid;
each B is independently a natural or non-natural amino acid, amino acid analog,
[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being optionally substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 ;
L is a macrocycle-forming linker of the formula
each L 1 , L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, C(═O)—O—, or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR E , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000;
w is an integer from 1-1000;
x is an integer from 0-10;
y is an integer from 0-10;
z is an integer from 0-10; and
n is an integer from 1-5,
wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.
35. The peptidomimetic macrocycle of claim 34 , wherein L 1 or L 2 is alkylene.
36. The peptidomimetic macrocycle of claim 34 , wherein one of A, B, or C is a non-natural amino acid.
37. The peptidomimetic macrocycle of claim 34 , wherein R 1 and R 2 are independently alkyl, optionally substituted with halo-.
38. The peptidomimetic macrocycle of claim 34 , wherein at least one of R 1 and R 2 is methyl.
39. The peptidomimetic macrocycle of claim 34 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the peptidomimetic macrocycle is more stable than a corresponding α-helical secondary structure of a corresponding non-macrocyclic polypeptide.
40. The peptidomimetic macrocycle of claim 34 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the macrocycle-forming linker spans from 1 turn to 5 turns of the peptidomimetic macrocycle.
41. The peptidomimetic macrocycle of claim 34 , wherein the macrocycle comprises a ring of about 18 atoms to 26 atoms.