Bis-sulfhydryl macrocyclization systems

1. A peptidomimetic macrocycle of Formula (I):

wherein:

each A, C, D, and E is independently a natural or non-natural amino acid;

B is a natural or non-natural amino acid, an amino acid comprising one or more additional methylene groups between the amino and carboxyl group, an amino acid comprising an amino group which is a secondary or tertiary amine, an amino acid comprising a carboxy group replaced by an ester,

 [—NH-L 4 -CO—], [—NH-L 4 —SO 2 —], or [—NH-L 4 -];

R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R 5 ;

L 1 , L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, heterocycloalkylene, or [—R 4 —K—R 4 —]n, each being unsubstituted or substituted with R 5 ;

K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;

each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

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 label, a radioisotope or a therapeutic agent;

each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent label, a radioisotope or a therapeutic agent;

R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, unsubstituted or 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, unsubstituted or 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;

n is an integer from 1-5;

x+y+z is at least 3; and

wherein the peptidomimetic macrocycle comprises an alpha-helix, wherein a secondary structure of the peptidomimetic macrocycle is more stable than a corresponding secondary structure of a corresponding non-macrocyclic polypeptide, and wherein the non-macrocyclic polypeptide lacks [-L 2 -].

2. 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, unsubstituted or substituted with halo-.

3. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

4. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is alkyl, unsubstituted or substituted with halo-.

5. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, unsubstituted or 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 R 1 and R 2 are methyl.

8. The peptidomimetic macrocycle of claim 1 , wherein at least one of D and E is a natural or unnatural amino acid substituted with a high molecular weight lipid or hydrocarbon.

9. The peptidomimetic macrocycle of claim 1 , wherein at least one of D and E is attached to an additional macrocyle-forming linker of formula [-L 1 -S-L 2 -S-L 3 -].

10. The peptidomimetic macrocycle of claim 1 , wherein the alpha-helix comprises from 1 turn to 5 turns.

11. The peptidomimetic macrocycle of claim 1 , wherein the alpha-helix is more stable than an α-helix of a corresponding non-macrocyclic polypeptide.

12. The peptidomimetic macrocycle of claim 1 , wherein [-L 1 -S-L 2 -S-L 3 -] spans from 1 turn to 5 turns of the alpha-helix.

13. The peptidomimetic macrocycle of claim 1 , wherein [-L 1 -S-L 2 -S-L 3 -] spans approximately 1, 2, 3, 4 or 5 turns of the alpha-helix.

14. The peptidomimetic macrocycle of claim 1 , wherein the length of [-L 1 -S-L 2 -S-L 3 -] is about 5 Å to about 9 Å per turn of the alpha-helix.

15. The peptidomimetic macrocycle of claim 1 , wherein [-L 1 -S-L 2 -S-L 3 -] spans approximately 1 turn of the alpha-helix.

16. The peptidomimetic macrocycle of claim 15 wherein the length of [-L 1 -S-L 2 -S-L 3 -] is approximately equal to the length of from about 5 carbon-carbon bonds to about 13 carbon-carbon bonds.

17. The peptidomimetic macrocycle of claim 15 wherein the length of [-L 1 -S-L 2 -S-L 3 -] is approximately equal to the length of from about 7 carbon-carbon bonds to about 10 carbon-carbon bonds.

18. The peptidomimetic macrocycle of claim 15 wherein the macrocycle comprises a ring of about 17 atoms to 25 atoms.

19. The peptidomimetic macrocycle of claim 1 , wherein the alpha-helix comprises about 2 turns.

20. The peptidomimetic macrocycle of claim 19 wherein the length of [-L 1 -S-L 2 -S-L 3 -] is approximately equal to the length of from about 8 carbon-carbon bonds to about 16 carbon-carbon bonds.

21. The peptidomimetic macrocycle of claim 19 wherein the length of [-L 1 -S-L 2 -S-L 3 -] is approximately equal to the length of from about 10 carbon-carbon bonds to about 13 carbon-carbon bonds.

22. The peptidomimetic macrocycle of claim 19 wherein the macrocycle comprises a ring of about 29 atoms to about 37 atoms.