THERAPEUTIC PEPTIDOMIMETIC MACROCYCLES

1 - 87 . (canceled)

88 . A peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises a polypeptide and a crosslinker connecting two amino acid residues of the polypeptide and has a formula of:

wherein:

the polypeptide is at least 60% identical to an amino acid sequence IWIAQALRRIGDEFNAYYARR (SEQ ID NO:120);

“AA” is a natural or non-natural amino acid side chain;

“ ” is [D] v or [E] w ;

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

each v and w is independently an integer from 1-1000;

each R 1 and R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-;

each L is independently a crosslinker of a formula -L 1 -L 2 - or a formula -L 1 -L 2 -L 3 -; and

each L 1 and L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.

89 . The peptidomimetic macrocycle of claim 88 , wherein the peptidomimetic macrocycle is at least 80% identical to the amino acid sequence.

90 . The peptidomimetic macrocycle of claim 88 , wherein the peptidomimetic macrocycle comprises an alpha helix.

91 . The peptidomimetic macrocycle of claim 88 , wherein L is the formula -L 1 -L 2 -.

92 . The peptidomimetic macrocycle of claim 91 , wherein each L 1 and L 2 is independently C 3 -C 6 alkylene.

93 . The peptidomimetic macrocycle of claim 91 , wherein each L 1 and L 2 is independently C 3 -C 6 alkenylene.

94 . The peptidomimetic macrocycle of claim 88 , wherein L is the formula -L 1 -L 2 -L 3 -, and each L 1 and L 3 is independently C 3 -C 6 alkylene, and L 2 is heteroarylene.

95 . The peptidomimetic macrocycle of claim 88 , wherein at least one of R 1 and R 2 is alkyl, unsubstituted or substituted with halo-.

96 . The peptidomimetic macrocycle of claim 88 , wherein R 1 and R 2 are independently alkyl, unsubstituted or substituted with halo-.

97 . The peptidomimetic macrocycle of claim 88 , wherein at least one of R 1 and R 2 is methyl.

98 . The peptidomimetic macrocycle of claim 88 , wherein R 1 and R 2 are methyl.

99 . The peptidomimetic macrocycle of claim 88 , wherein R 1 and R 2 are H.

100 . A method of treating a disorder in a human subject in need thereof, comprising administering to the subject a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises a polypeptide and a crosslinker connecting two amino acid residues of the polypeptide and has a formula of:

wherein:

the polypeptide is at least 60% identical to an amino acid sequence IWIAQALRRIGDEFNAYYARR (SEQ ID NO:120);

“AA” is a natural or non-natural amino acid side chain;

“ ” is [D] v or [E] w ;

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

each v and w is independently an integer from 1-1000;

each R 1 and R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-;

each L is independently a crosslinker of the formula -L 1 -L 2 - or the formula -L 1 -L 2 -L 3 -; and

each L 1 and L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.

101 . The method of claim 100 , wherein the disorder is a cancer.

102 . The method of claim 101 , wherein the cancer is an ovarian cancer, skin cancer, prostate cancer, renal cancer, breast cancer, pancreatic cancer, small-cell lung cancer, colon cancer, liver cancer, Multiple myeloma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) of T cell lineage or B cell lineage or mixed lineage, Chronic lymphocytic leukemia (CLL), Ph+ acute lymphocytic leukemia, Cutaneous T cell lymphoma (CTCL), Acute myelocytic leukemia (AML), Chronic Myelocytic leukemia, or follicular lymphoma.

103 . The method of claim 101 , wherein the cancer is resistant to ABT-737 or an analog thereof.

104 . The method of claim 100 , wherein the disorder is a metabolic disorder.

105 . The method of claim 100 , wherein the disorder is an immunoproliferative disorder.

106 . The method of claim 100 , wherein the administering is in conjunction with a standard method of care that is chemotherapy, radiation therapy, or surgery.

107 . A method of preparing a peptidomimetic macrocycle, comprising:

(a) preparing a peptidomimetic macrocycle by crosslinking two amino acid residues of a polypeptide to stabilize a secondary structure of the peptidomimetic macrocycle;

(b) testing the peptidomimetic macrocycle for a reduced antibody response in an in vivo assay as compared to a corresponding uncrosslinked polypeptide; and

(c) selecting the tested peptidomimetic macrocycle as the therapeutic peptidomimetic macrocycle if the tested peptidomimetic macrocycle has a reduced immune response relative to the corresponding uncrosslinked polypeptide; and

wherein the peptidomimetic macrocycle has a formula of:

wherein:

the polypeptide is at least 60% identical to an amino acid sequence

(SEQ ID NO: 120)

IWIAQALRRIGDEFNAYYARR;

“AA” is a natural or non-natural amino acid side chain;

“ ” is [D] v or [E] w ;

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

each v and w is independently an integer from 1-1000;

each R 1 and R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-;

each L is independently a crosslinker of the formula -L 1 -L 2 - or the formula -L 1 -L 2 -L 3 -; and

each L 1 and L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.