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 unsubstituted or 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 triazole-containing 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 alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is O, S, SO, SO 2 , CO, C(═O)—O—[[CO 2 ]], 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+y+z is 3, 4, 5, 6, 7, 8, 9, or 10; and
n is an integer from 1-5.
2. The peptidomimetic macrocycle of claim 1 , wherein x+y+z is 3.
3. The peptidomimetic macrocycle of claim 1 , wherein x+y+z is 6.
4. The peptidomimetic macrocycle of claim 1 , wherein L is
5. The peptidomimetic macrocycle of claim 1 , wherein L is
6. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being unsubstituted or substituted with halo-.
7. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being unsubstituted or substituted with halo-.
8. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is alkyl, each non-H group being unsubstituted or substituted with halo-.
9. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, each non-H group being unsubstituted or substituted with halo-.
10. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is methyl.
11. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are methyl.
12. The peptidomimetic macrocycle of claim 1 , wherein at least one of D and E is attached to an additional macrocycle-forming linker.
13. The peptidomimetic macrocycle of claim 1 , wherein a secondary structure of the peptidomimetic macrocycle is more stable than a corresponding secondary structure of a corresponding non-macrocyclic polypeptide.
14. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased thermal stability compared to a corresponding non-macrocyclic polypeptide.
15. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased biological activity compared to a corresponding non-macrocyclic polypeptide.
16. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased resistance to proteolytic degradation compared to a corresponding non-macrocyclic polypeptide.
17. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased ability to penetrate living cells compared to a corresponding non-macrocyclic polypeptide.
18. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.
19. The peptidomimetic macrocycle of claim 18 , wherein the α-helix comprises from 1 turn to 5 turns.
20. The peptidomimetic macrocycle of claim 18 , wherein the α-helix is more stable than an α-helix of a corresponding non-macrocyclic polypeptide.
21. The peptidomimetic macrocycle of claim 18 , wherein the macrocycle-forming linker spans from 1 turn to 5 turns of the α-helix.
22. The peptidomimetic macrocycle of claim 18 , wherein the macrocycle-forming linker spans approximately 1 turn to approximately 2 turns of the α-helix.
23. The peptidomimetic macrocycle of claim 18 , 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.