Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology t
Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.
대표청구항▼
1. A peptidomimetic macrocycle of Formula: or a pharmaceutically-acceptable salt thereof wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is independently an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid a
1. A peptidomimetic macrocycle of Formula: or a pharmaceutically-acceptable salt thereof wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is independently an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO: 9), where each of X4 and X11 is independently an amino acid;each D is independently an amino acid;each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; each L and L′ is independently a macrocycle-forming linker of the formula -L1-L2-;each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4-K-R4-]n, each being optionally substituted with R5;each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;R5 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;v is an integer from 1-1000;w is an integer from 3-1000; andn is an integer from 1-5. 2. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, wherein the peptidomimetic macrocycle has the formula: or a pharmaceutically-acceptable salt thereof, wherein: each A, C, and D is independently an amino acid;each B is independently an amino acid, [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-]; each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each L and L′ is independently a macrocycle-forming linker of the formula -L1-L2-;each L1 and L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4-K-R4—]n, each being optionally substituted with R5; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v is independently an integer from 1-1000;each w is independently an integer from 3-1000;u is an integer from 1-10;each x, y and z is independently an integer from 0-10; andeach n is independently an integer from 1-5. 3. A peptidomimetic macrocycle of Formula: or pharmaceutically-acceptable salt thereof wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xa10 is independently an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acids as the amino acid at the corresponding position of the sequence Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12 (SEQ ID NO: 8) or Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO: 9), wherein each X4 and X11 is independently an amino acid;each D is independently an amino acid;each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;each L or L′ is independently a macrocycle-forming linker;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SO2R6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;v is an integer from 1-1000; andw is an integer from 3-1000. 4. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycles wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 5. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomirnetic macrocycle or pharmaceutically-acceptable salt thereof has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 6. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved in vitro anti-tumor efficacy against a p53 positive tumor cell line relative to a corresponding peptidomimetic macrocycle1 wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 7. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved in vitro induction of apoptosis in a p53 positive tumor cell line relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 8. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved in vitro anti-tumor efficacy ratio for a p53 positive versus a p53 negative or a p53 mutant tumor cell line relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 9. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved in vivo anti-tumor efficacy against a p53 positive tumor relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 10. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved in vivo induction of apoptosis in a p53 positive tumor relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 11. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved cell permeability relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the corresponding peptidomimetic macrocycle. 12. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved solubility relative to a corresponding peptidomimetic macrocycle, wherein w is 0, 1 or 2 in the correspondingpeptidomimetic macrocycle. 13. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1 or 3, wherein Xaa5 is Glu. 14. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 13, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof has an improved property relative to a corresponding peptidomimetic macrocycle, wherein the improved property is selected from the group consisting of improved binding affinity, improved solubility, improved cellular efficacy, improved helicity, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, and improved induction of apoptosis, wherein Xaa5 is Ala in the corresponding peptidomimetic macrocycle. 15. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein [D]v is -Leu1Thr2. 16. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein w is 3-10. 17. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 16, wherein w is 3-6. 18. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 16, wherein w is 6-10. 19. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 16, wherein w is 6. 20. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1 or 3, wherein v is 1-10. 21. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 20, wherein v is 2-10. 22. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 20, wherein v is 2-5. 23. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 20, wherein v is 2. 24. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein [D]v is -Leu1-Thr2. 25. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, or heterocycloarylene, each being optionally substituted with R5. 26. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein each L1 and L2 is are independently alkylene or alkenylene. 27. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein L is alkylene, alkenylene, or alkynylene. 28. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 2, 27, and 3 wherein L is alkenylene. 29. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 28, wherein L is C3-C16 alkenylene. 30. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 29, wherein L is C10-C14 alkenylene. 31. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 32. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein R1 and R2 are H. 33. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 1, wherein R1 and R2 are independently alkyl. 34. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 33, wherein R1 and R2 are methyl. 35. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein x+y+z=6. 36. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein u is 1. 37. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2, and 3, wherein each E is independently Ser or Ala. 38. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 39. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 40. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 41. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 42. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 43. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 44. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 45. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 46. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 47. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 48. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 49. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 50. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 51. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 52. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 53. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 54. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 55. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 56. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 57. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 58. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 59. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 60. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 61. The peptidomimetic macrocycle of claim 1, having formula: or a pharmaceutically acceptable salt thereof. 62. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 16, wherein w is 3. 63. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein v is 1-10. 64. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein v is 3-10. 65. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein v is 3-5. 66. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein v is 3. 67. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 2, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is at least about 80% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c. 68. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 67, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is at least about 90% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c. 69. The peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of claim 68, wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is at least about 95% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c. 70. A method of treating cancer in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2 and 3. 71. The method of claim 70, wherein the cancer is selected from the group consisting of head and neck cancer, melanoma, lung cancer, breast cancer, and glioma. 72. A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2 and 3. 73. A method of antagonizing the interaction between p53 and MDM2 proteins and/or between p53 and MDMX proteins in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of any one of claims 1, 2 and 3. 74. A method of preparing a composition comprising a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of Formula (Ia): or pharmaceutically-acceptable salt thereof, comprising an amino acid sequence which is about 60% to about 100% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, the method comprising treating a compound of Formula (II) or pharmaceutically-acceptable salt thereof with a catalyst to result in the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof, wherein in the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof and in the compound of Formula (II) or pharmaceutically-acceptable salt thereof each A, C, and D is independently an amino acid; each B is independently an amino acid [—NH-L3-SO2—], or [—NH-L3-];each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);each R1 and R2 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen; or forms a macrocycle-forming linker L′ connected to the alpha position of one of the D or E amino acids;each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each L′ is independently a macrocycle-forming linker of the formula -L1-L2-;each L1, L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4-K-R4—]n, each being optionally substituted with R5; each R4 and R4′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v is independently an integer from 1-1000;each w is independently an integer from 3-1000;u is an integer from 1-10;each x, y and z is independently an integer from 0-10;each n is independently an integer from 1-5;each o is independently an integer from 1 to 15;each p is independently an integer from 1 to 15;(E) indicates a trans double bond or an E-double bond; andone or more of A, B, and C, has a side chain bearing a protecting group. 75. The method of claim 74, wherein the protecting group is a nitrogen atom protecting group. 76. The method of claim 74, wherein the protecting group is a Boc group. 77. The method of claim 75, wherein the side chain bearing the protecting group comprises a protected indole. 78. The method of claim 77, wherein the protecting group is borne on the side chain of a tryptophan (W). 79. The method of claim 78, wherein the protecting group is a Boc group. 80. The method of claim 74, wherein after the step of treating the compound of Formula (II) or pharmaceutically-acceptable salt thereof with the catalyst, the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof is obtained in an amount equal or higher than an amount obtained of a corresponding compound which is a Z isomer. 81. The method of claim 80, wherein after the step of treating the compound of Formula (II) or pharmaceutically-acceptable salt thereof with the catalyst, the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof is obtained in an amount that is 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold higher than an amount obtained of the corresponding compound which is the Z isomer. 82. The method of claim 74, wherein the catalyst is a ruthenium catalyst. 83. The method of claim 74, further comprising the step of treating the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof with a reducing agent or an oxidizing agent. 84. The method of claim 74, wherein the compound of Formula (II) or parmaceutically-acceptable salt thereof is further attached to a solid support. 85. The method of claim 74, wherein the compound of Formula (II) or pharmaceutically-acceptable salt thereof is not attached to a solid support. 86. The method of claim 74, further comprising removing the protecting group from the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof. 87. The method of claim 74, wherein the treating is conducted at a temperature ranging from about 20° C. to about 80° C. 88. The method of claim 74, wherein the peptidomimetic macrocycle of Formula (Ia) has the Formula: or pharmaceutically-acceptable salt thereof, wherein: each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is independently an amino acid, wherein at least two of Xaa3, Xaa5, Xaa6, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12(SEQ ID NO: 8), wherein each of X4 and X11 is independently an amino acid;v is an integer from 1-500;Xaa7 is Boc-protected tryptophan. 89. The method of claim 74, wherein the peptidomimetic macrocycle of Formula (Ia) has the Formula: or pharmaceutically-acceptable salt thereof, wherein: each of Xaa3, Xaa8, Xaa6, Xaa7, Xaa8, Xaa9, and Xaar10 is independently an amino acid, wherein at least two of Xaa3, Xaa5, Xaa6, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO: 9), wherein each of X4 and X11 is independently an amino acid;comprises double bond in the E configuration;v is an integer from 1-500; andXaa7 is Boc-protected tryptophan. 90. The method of claim 74, wherein the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically-acceptable salt thereof comprises an α-helix. 91. The method of claim 77 or 78, wherein L is C3-C16 alkenylene. 92. The method of claim 91, wherein L is C10-C14 alkenylene. 93. The method of claim 74, wherein w is 3-10. 94. The method of claim 74, wherein w is 3-6. 95. The method of claim 74, wherein w is 3. 96. The method of claim 74, wherein v is 1-10. 97. The method of claim 74, wherein v is 3-10. 98. The method of claim 74, wherein v is 3-5. 99. The method of claim 74, wherein v is 3. 100. The method of claim 74, wherein x+y+z=6 in the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically-acceptable salt thereof. 101. The method of claim 74, wherein u is 1. 102. The method of claim 74, wherein each E is independently an amino acid selected from the group consisting of Ser and Ala. 103. The method of claim 74, wherein the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is about 80% to about 100% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c. 104. The method of claim 103, wherein the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is about 90% to about 100% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c. 105. The method of claim 104, wherein the peptidomimetic macrocycle of Formula (Ia) or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is about 95% to about 100% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c.
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