Patent Publication Number: US-2017360881-A1

Title: Peptidomimetic macrocycles and uses thereof

Description:
CROSS REFERENCE 
     This Application claims the benefit of U.S. Provisional Application No. 62/351,480, filed Jun. 17, 2016, which is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND 
     Increasing antibacterial resistance presents a major challenge in antibiotic discovery. The discovery of new antibiotics with new mechanisms of action is an important goal in antibiotic research that is crucial for combating infections caused by pathogens, such as multidrug-resistant bacteria. The unique asymmetric outer membrane in Gram-negative microorganisms is a possible target. The outer membrane acts as a permeability barrier that protects the cell from external stressors, such as antibiotics. 
     INCORPORATION BY REFERENCE 
     All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 
     SUMMARY OF THE INVENTION 
     In some embodiments, the invention provides a method of treating a microbial infection, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a peptidomimetic macrocycle with at least 6 amino acid residues. 
     In some embodiments, the invention provides a peptidomimetic macrocycle comprising an amino acid sequence with at least about 60% homology to SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6. 
     In some embodiments, the invention provides a method of treating a microbial infection, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a peptidomimetic macrocycle with an amino acid sequence with at least about 60% homology to SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6. 
     In some embodiments, the invention provides a peptidomimetic macrocycle of the formula: 
     
       
         
         
             
             
         
       
     
     wherein: each L is independently a macrocycle-forming linker; each AA 1  to AA 20  is independently a natural or non-natural amino acid; each z 1  to z 20  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the sum of z 1  to z 20  is at least 6; and R q  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cyclo aryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with a neighboring amino acid; or a pharmaceutically-acceptable salt thereof. 
     In some embodiments, the invention provides a method of treating a microbial infection, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a peptidomimetic macrocycle of the formula: 
     
       
         
         
             
             
         
       
     
     wherein: each L is independently a macrocycle-forming linker; each AA 1  to AA 20  is independently a natural or non-natural amino acid; each z 1  to z 20  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the sum of z 1  to z 20  is at least 6; and R q  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cyclo aryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with a neighboring amino acid; or a pharmaceutically-acceptable salt thereof. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts the transport of lipopolysaccharide in  P. aeruginosa.    
         FIG. 2  illustrates the barrel and plug architecture of an LptD-LptE complex. 
         FIG. 3  illustrates the potential hydrophobic residues of LptE for lipopolysaccharide binding. 
     
    
    
     DETAILED DESCRIPTION 
     As used herein, the term “macrocycle” refers to a molecule having a chemical structure including a ring or cycle formed by at least 9 covalently bonded atoms. 
     As used herein, the term “peptidomimetic macrocycle” or “crosslinked polypeptide” refers to a compound comprising a plurality of amino acid residues joined by a plurality of peptide bonds and at least one macrocycle-forming linker that forms a macrocycle between a first naturally-occurring or non-naturally-occurring amino acid residue (or analog) and a second naturally-occurring or non-naturally-occurring amino acid residue (or analog) within the same molecule. Peptidomimetic macrocycles include embodiments where the macrocycle-forming linker connects the α-carbon of a first amino acid residue (or analog) to the α-carbon of a second amino acid residue (or analog). The peptidomimetic macrocycles optionally include one or more non-peptide bonds between one or more amino acid residues and/or amino acid analog residues, and optionally include one or more non-naturally-occurring amino acid residues or amino acid analog residues in addition to any non-peptide bonds that form the macrocycle. A “corresponding uncrosslinked polypeptide” when referred to in the context of a peptidomimetic macrocycle is understood to relate to a polypeptide of the same length as the macrocycle and comprising the equivalent natural amino acids of the wild-type sequence corresponding to the macrocycle. 
     As used herein, the term “stability” refers to the maintenance of a defined secondary structure in solution by a peptidomimetic macrocycle as measured by circular dichroism, NMR or another biophysical measure, or refers to resistance to proteolytic degradation in vitro or in vivo. Non-limiting examples of secondary structures contemplated herein are α-helices, 3 10  helices, β-turns (including β-hairpins), and β-pleated sheets. 
     As used herein, the term “helical stability” refers to the maintenance of an α-helical structure by a peptidomimetic macrocycle as measured by circular dichroism or NMR. For example, in some embodiments, a peptidomimetic macrocycle exhibits at least a 1.25, 1.5, 1.75, or 2-fold increase in α-helicity as determined by circular dichroism compared to a corresponding uncrosslinked macrocycle. 
     The term “amino acid” refers to a molecule containing both an amino group and a carboxyl group. Suitable amino acids include, without limitation, both the D- and L-isomers of naturally-occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. The term amino acid, as used herein, includes, without limitation, α-amino acids, natural amino acids, non-natural amino acids, and amino acid analogs. 
     The term “α-amino acid” refers to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the α-carbon. 
     The term “β-amino acid” refers to a molecule containing both an amino group and a carboxyl group in a β configuration. 
     The term “naturally occurring amino acid” refers to any one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. 
     The following table shows a summary of the properties of natural amino acids: 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                 Hydrop- 
               
               
                   
                 3-Letter 
                 1-Letter 
                 Side-chain 
                 Side-chain 
                 athy 
               
               
                 Amino Acid 
                 Code 
                 Code 
                 Polarity 
                 charge (pH 7.4) 
                 Index 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Alanine 
                 Ala 
                 A 
                 nonpolar 
                 neutral 
                 1.8 
               
               
                 Arginine 
                 Arg 
                 R 
                 polar 
                 positive 
                 −4.5 
               
               
                 Asparagine 
                 Asn 
                 N 
                 polar 
                 neutral 
                 −3.5 
               
               
                 Aspartic acid 
                 Asp 
                 D 
                 polar 
                 negative 
                 −3.5 
               
               
                 Cysteine 
                 Cys 
                 C 
                 polar 
                 neutral 
                 2.5 
               
               
                 Glutamic acid 
                 Glu 
                 E 
                 polar 
                 negative 
                 −3.5 
               
               
                 Glutamine 
                 Gln 
                 Q 
                 polar 
                 neutral 
                 −3.5 
               
               
                 Glycine 
                 Gly 
                 G 
                 nonpolar 
                 neutral 
                 −0.4 
               
               
                 Histidine 
                 His 
                 H 
                 polar 
                 positive (10%) 
                 −3.2 
               
               
                   
                   
                   
                   
                 neutral (90%) 
               
               
                 Isoleucine 
                 Ile 
                 I 
                 nonpolar 
                 neutral 
                 4.5 
               
               
                 Leucine 
                 Leu 
                 L 
                 nonpolar 
                 neutral 
                 3.8 
               
               
                 Lysine 
                 Lys 
                 K 
                 polar 
                 positive 
                 −3.9 
               
               
                 Methionine 
                 Met 
                 M 
                 nonpolar 
                 neutral 
                 1.9 
               
               
                 Phenylalanine 
                 Phe 
                 F 
                 nonpolar 
                 neutral 
                 2.8 
               
               
                 Proline 
                 Pro 
                 P 
                 nonpolar 
                 neutral 
                 −1.6 
               
               
                 Serine 
                 Ser 
                 S 
                 polar 
                 neutral 
                 −0.8 
               
               
                 Threonine 
                 Thr 
                 T 
                 polar 
                 neutral 
                 −0.7 
               
               
                 Tryptophan 
                 Trp 
                 W 
                 nonpolar 
                 neutral 
                 −0.9 
               
               
                 Tyrosine 
                 Tyr 
                 Y 
                 polar 
                 neutral 
                 −1.3 
               
               
                 Valine 
                 Val 
                 V 
                 nonpolar 
                 neutral 
                 4.2 
               
               
                   
               
            
           
         
       
     
     “Hydrophobic amino acids” include small hydrophobic amino acids and large hydrophobic amino acids. “Small hydrophobic amino acids” are glycine, alanine, proline, and analogs thereof. “Large hydrophobic amino acids” are valine, leucine, isoleucine, phenylalanine, methionine, tryptophan, and analogs thereof. “Polar amino acids” are serine, threonine, asparagine, glutamine, cysteine, tyrosine, and analogs thereof. “Charged amino acids” are lysine, arginine, histidine, aspartate, glutamate, and analogs thereof. 
     The term “amino acid analog” refers to a molecule which is structurally similar to an amino acid and which can be substituted for an amino acid in the formation of a peptidomimetic macrocycle. Amino acid analogs include, without limitation, β-amino acids and amino acids where the amino or carboxy group is substituted by a similarly reactive group (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution of the carboxy group with an ester). 
     The term “non-natural amino acid” refers to an amino acid which is not one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. Non-natural amino acids or amino acid analogs include, without limitation, structures according to the following: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Amino acid analogs include β-amino acid analogs. Examples of β-amino acid analogs include, but are not limited to, the following: cyclic β-amino acid analogs; β-alanine; (R)-β-phenylalanine; (R)-1,2,3,4-tetrahydro-isoquinoline-3-acetic acid; (R)-3-amino-4-(1-naphthyl)-butyric acid; (R)-3-amino-4-(2,4-dichlorophenyl)butyric acid; (R)-3-amino-4-(2-chlorophenyl)-butyric acid; (R)-3-amino-4-(2-cyanophenyl)-butyric acid; (R)-3-amino-4-(2-fluorophenyl)-butyric acid; (R)-3-amino-4-(2-furyl)-butyric acid; (R)-3-amino-4-(2-methylphenyl)-butyric acid; (R)-3-amino-4-(2-naphthyl)-butyric acid; (R)-3-amino-4-(2-thienyl)-butyric acid; (R)-3-amino-4-(2-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-(3,4-dichlorophenyl)butyric acid; (R)-3-amino-4-(3,4-difluorophenyl)butyric acid; (R)-3-amino-4-(3-benzothienyl)-butyric acid; (R)-3-amino-4-(3-chlorophenyl)-butyric acid; (R)-3-amino-4-(3-cyanophenyl)-butyric acid; (R)-3-amino-4-(3-fluorophenyl)-butyric acid; (R)-3-amino-4-(3-methylphenyl)-butyric acid; (R)-3-amino-4-(3-pyridyl)-butyric acid; (R)-3-amino-4-(3-thienyl)-butyric acid; (R)-3-amino-4-(3-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-(4-bromophenyl)-butyric acid; (R)-3-amino-4-(4-chlorophenyl)-butyric acid; (R)-3-amino-4-(4-cyanophenyl)-butyric acid; (R)-3-amino-4-(4-fluorophenyl)-butyric acid; (R)-3-amino-4-(4-iodophenyl)-butyric acid; (R)-3-amino-4-(4-methylphenyl)-butyric acid; (R)-3-amino-4-(4-nitrophenyl)-butyric acid; (R)-3-amino-4-(4-pyridyl)-butyric acid; (R)-3-amino-4-(4-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-pentafluoro-phenylbutyric acid; (R)-3-amino-5-hexenoic acid; (R)-3-amino-5-hexynoic acid; (R)-3-amino-5-phenylpentanoic acid; (R)-3-amino-6-phenyl-5-hexenoic acid; (S)-1,2,3,4-tetrahydro-isoquinoline-3-acetic acid; (S)-3-amino-4-(1-naphthyl)-butyric acid; (S)-3-amino-4-(2,4-dichlorophenyl)butyric acid; (S)-3-amino-4-(2-chlorophenyl)-butyric acid; (S)-3-amino-4-(2-cyanophenyl)-butyric acid; (S)-3-amino-4-(2-fluorophenyl)-butyric acid; (S)-3-amino-4-(2-furyl)-butyric acid; (S)-3-amino-4-(2-methylphenyl)-butyric acid; (S)-3-amino-4-(2-naphthyl)-butyric acid; (S)-3-amino-4-(2-thienyl)-butyric acid; (S)-3-amino-4-(2-trifluoromethylphenyl)-butyric acid; (S)-3-amino-4-(3,4-dichlorophenyl)butyric acid; (S)-3-amino-4-(3,4-difluorophenyl)butyric acid; (S)-3-amino-4-(3-benzothienyl)-butyric acid; (S)-3-amino-4-(3-chlorophenyl)-butyric acid; (S)-3-amino-4-(3-cyanophenyl)-butyric acid; (S)-3-amino-4-(3-fluorophenyl)-butyric acid; (S)-3-amino-4-(3-methylphenyl)-butyric acid; (S)-3-amino-4-(3-pyridyl)-butyric acid; (S)-3-amino-4-(3-thienyl)-butyric acid; (S)-3-amino-4-(3-trifluoromethylphenyl)-butyric acid; (S)-3-amino-4-(4-bromophenyl)-butyric acid; (S)-3-amino-4-(4-chlorophenyl)-butyric acid; (S)-3-amino-4-(4-cyanophenyl)-butyric acid; (S)-3-amino-4-(4-fluorophenyl)-butyric acid; (S)-3-amino-4-(4-iodophenyl)-butyric acid; (S)-3-amino-4-(4-methylphenyl)-butyric acid; (S)-3-amino-4-(4-nitrophenyl)-butyric acid; (S)-3-amino-4-(4-pyridyl)-butyric acid; (S)-3-amino-4-(4-trifluoromethylphenyl)-butyric acid; (S)-3-amino-4-pentafluoro-phenylbutyric acid; (S)-3-amino-5-hexenoic acid; (S)-3-amino-5-hexynoic acid; (S)-3-amino-5-phenylpentanoic acid; (S)-3-amino-6-phenyl-5-hexenoic acid; 1,2,5,6-tetrahydropyridine-3-carboxylic acid; 1,2,5,6-tetrahydropyridine-4-carboxylic acid; 3-amino-3-(2-chlorophenyl)-propionic acid; 3-amino-3-(2-thienyl)-propionic acid; 3-amino-3-(3-bromophenyl)-propionic acid; 3-amino-3-(4-chlorophenyl)-propionic acid; 3-amino-3-(4-methoxyphenyl)-propionic acid; 3-amino-4,4,4-trifluoro-butyric acid; 3-aminoadipic acid; D-β-phenylalanine; β-leucine; L-β-homoalanine; L-β-homoaspartic acid γ-benzyl ester; L-β-homoglutamic acid δ-benzyl ester; L-β-homoisoleucine; L-β-homoleucine; L-β-homomethionine; L-β-homophenylalanine; L-β-homoproline; L-β-homotryptophan; L-β-homovaline; L-Nω-benzyloxycarbonyl-β-homolysin; Nω-L-β-homoarginine; O-benzyl-L-β-homohydroxyproline; O-benzyl-L-β-homoserine; O-benzyl-L-β-homothreonine; O-benzyl-L-β-homotyrosine; γ-trityl-L-β-homoasparagine; (R)-β-phenylalanine; L-β-homoaspartic acid γ-t-butyl ester; L-β-homoglutamic acid δ-t-butyl ester; L-Nω-β-homolysine; Nδ-trityl-L-β-homoglutamine; Nω-2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl-L-β-homoarginine; O-t-butyl-L-β-homohydroxy-proline; O-t-butyl-L-β-homoserine; O-t-butyl-L-β-homothreonine; O-t-butyl-L-β-homotyrosine; 2-aminocyclopentane carboxylic acid; and 2-aminocyclohexane carboxylic acid. 
     Amino acid analogs include analogs of alanine, valine, glycine or leucine. Examples of amino acid analogs of alanine, valine, glycine, and leucine include, but are not limited to, the following: α-methoxyglycine; α-allyl-L-alanine; α-aminoisobutyric acid; α-methyl-leucine; β-(1-naphthyl)-D-alanine; β-(1-naphthyl)-L-alanine; β-(2-naphthyl)-D-alanine; β-(2-naphthyl)-L-alanine; β-(2-pyridyl)-D-alanine; β-(2-pyridyl)-L-alanine; β-(2-thienyl)-D-alanine; β-(2-thienyl)-L-alanine; β-(3-benzothienyl)-D-alanine; β-(3-benzothienyl)-L-alanine; β-(3-pyridyl)-D-alanine; β-(3-pyridyl)-L-alanine; β-(4-pyridyl)-D-alanine; β-(4-pyridyl)-L-alanine; β-chloro-L-alanine; β-cyano-L-alanine; β-cyclohexyl-D-alanine; β-cyclohexyl-L-alanine; β-cyclopenten-l-yl-alanine; β-cyclopentyl-alanine; β-cyclopropyl-L-Ala-OH.dicyclohexylammonium salt; β-t-butyl-D-alanine; β-t-butyl-L-alanine; γ-aminobutyric acid; L-α,β-diaminopropionic acid; 2,4-dinitro-phenylglycine; 2,5-dihydro-D-phenylglycine; 2-amino-4,4,4-trifluorobutyric acid; 2-fluoro-phenylglycine; 3-amino-4,4,4-trifluoro-butyric acid; 3-fluoro-valine; 4,4,4-trifluoro-valine; 4,5-dehydro-L-leu-OH.dicyclohexylammonium salt; 4-fluoro-D-phenylglycine; 4-fluoro-L-phenylglycine; 4-hydroxy-D-phenylglycine; 5,5,5-trifluoro-leucine; 6-aminohexanoic acid; cyclopentyl-D-Gly-OH.dicyclohexylammonium salt; cyclopentyl-Gly-OH.dicyclohexylammonium salt; D-α,β-diaminopropionic acid; D-α-aminobutyric acid; D-α-t-butylglycine; D-(2-thienyl)glycine; D-(3-thienyl)glycine; D-2-aminocaproic acid; D-2-indanylglycine; D-allylglycine.dicyclohexylammonium salt; D-cyclohexylglycine; D-norvaline; D-phenylglycine; β-aminobutyric acid; β-aminoisobutyric acid; (2-bromophenyl)glycine; (2-methoxyphenyl)glycine; (2-methylphenyl)glycine; (2-thiazoyl)glycine; (2-thienyl)glycine; 2-amino-3-(dimethylamino)-propionic acid; L-α,β-diaminopropionic acid; L-α-aminobutyric acid; L-α-t-butylglycine; L-(3-thienyl)glycine; L-2-amino-3-(dimethylamino)-propionic acid; L-2-aminocaproic acid dicyclohexyl-ammonium salt; L-2-indanylglycine; L-allylglycine.dicyclohexyl ammonium salt; L-cyclohexylglycine; L-phenylglycine; L-propargylglycine; L-norvaline; N-α-aminomethyl-L-alanine; D-α,γ-diaminobutyric acid; L-α,γ-diaminobutyric acid; β-cyclopropyl-L-alanine; (N-β-(2,4-dinitrophenyl))-L-α,β-diaminopropionic acid; (N-β-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-D-α,β-diaminopropionic acid; (N-β-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,β-diaminopropionic acid; (N-β-4-methyltrityl)-L-α,β-diaminopropionic acid; (N-β-allyloxycarbonyl)-L-α,β-diaminopropionic acid; (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-D-α,γ-diaminobutyric acid; (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,γ-diaminobutyric acid; (N-γ-4-methyltrityl)-D-α,γ-diaminobutyric acid; (N-γ-4-methyltrityl)-L-α,γ-diaminobutyric acid; (N-γ-allyloxycarbonyl)-L-α,γ-diaminobutyric acid; D-α,γ-diaminobutyric acid; 4,5-dehydro-L-leucine; cyclopentyl-D-Gly-OH; cyclopentyl-Gly-OH; D-allylglycine; D-homocyclohexylalanine; L-1-pyrenylalanine; L-2-aminocaproic acid; L-allylglycine; L-homocyclohexylalanine; and N-(2-hydroxy-4-methoxy-Bzl)-Gly-OH. 
     Amino acid analogs include analogs of arginine or lysine. Examples of amino acid analogs of arginine and lysine include, but are not limited to, the following: citrulline; L-2-amino-3-guanidinopropionic acid; L-2-amino-3-ureidopropionic acid; L-citrulline; Lys(Me) 2 -OH; Lys(N 3 )—OH; Nδ-benzyloxycarbonyl-L-ornithine; Nω-nitro-D-arginine; Nω-nitro-L-arginine; α-methyl-ornithine; 2,6-diaminoheptanedioic acid; L-ornithine; (Nδ-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)ethyl)-D-ornithine; (Nδ-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)ethyl)-L-ornithine; (Nδ-4-methyltrityl)-D-ornithine; (Nδ-4-methyltrityl)-L-ornithine; D-ornithine; L-ornithine; Arg(Me)(Pbf)-OH; Arg(Me) 2 -OH (asymmetrical); Arg(Me) 2 -OH (symmetrical); Lys(ivDde)-OH; Lys(Me) 2 -OH.HCl; Lys(Me 3 )-OH chloride; Nω-nitro-D-arginine; and Nω-nitro-L-arginine. 
     Amino acid analogs include analogs of aspartic or glutamic acids. Examples of amino acid analogs of aspartic and glutamic acids include, but are not limited to, the following: α-methyl-D-aspartic acid; α-methyl-glutamic acid; α-methyl-L-aspartic acid; γ-methylene-glutamic acid; (N-γ-ethyl)-L-glutamine; [N-α-(4-aminobenzoyl)]-L-glutamic acid; 2,6-diaminopimelic acid; L-α-aminosuberic acid; D-2-aminoadipic acid; D-α-aminosuberic acid; α-aminopimelic acid; iminodiacetic acid; L-2-aminoadipic acid; threo-β-methyl-aspartic acid; γ-carboxy-D-glutamic acid γ,γ-di-t-butyl ester; γ-carboxy-L-glutamic acid γ,γ-di-t-butyl ester; Glu(OAll)-OH; L-Asu(OtBu)-OH; and pyroglutamic acid. 
     Amino acid analogs include analogs of cysteine and methionine. Examples of amino acid analogs of cysteine and methionine include, but are not limited to, Cys(farnesyl)-OH, Cys(farnesyl)-OMe, α-methyl-methionine, Cys(2-hydroxyethyl)-OH, Cys(3-aminopropyl)-OH, 2-amino-4-(ethylthio)butyric acid, buthionine, buthioninesulfoximine, ethionine, methionine methylsulfonium chloride, selenomethionine, cysteic acid, [2-(4-pyridyl)ethyl]-DL-penicillamine, [2-(4-pyridyl)ethyl]-L-cysteine, 4-methoxybenzyl-D-penicillamine, 4-methoxybenzyl-L-penicillamine, 4-methylbenzyl-D-penicillamine, 4-methylbenzyl-L-penicillamine, benzyl-D-cysteine, benzyl-L-cysteine, benzyl-DL-homocysteine, carbamoyl-L-cysteine, carboxyethyl-L-cysteine, carboxymethyl-L-cysteine, diphenylmethyl-L-cysteine, ethyl-L-cysteine, methyl-L-cysteine, t-butyl-D-cysteine, trityl-L-homocysteine, trityl-D-penicillamine, cystathionine, homocystine, L-homocystine, (2-aminoethyl)-L-cysteine, seleno-L-cystine, cystathionine, Cys(StBu)-OH, and acetamidomethyl-D-penicillamine. 
     Amino acid analogs include analogs of phenylalanine and tyrosine. Examples of amino acid analogs of phenylalanine and tyrosine include β-methyl-phenylalanine, β-hydroxyphenylalanine, α-methyl-3-methoxy-DL-phenylalanine, α-methyl-D-phenylalanine, α-methyl-L-phenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2,4-dichloro-phenylalanine, 2-(trifluoromethyl)-D -phenylalanine, 2-(trifluoromethyl)-L-phenylalanine, 2-bromo-D-phenylalanine, 2-bromo-L-phenylalanine, 2-chloro-D-phenylalanine, 2-chloro-L-phenylalanine, 2-cyano-D-phenylalanine, 2-cyano-L-phenylalanine, 2-fluoro-D-phenylalanine, 2-fluoro-L-phenylalanine, 2-methyl-D-phenylalanine, 2-methyl-L-phenylalanine, 2-nitro-D-phenylalanine, 2-nitro-L-phenylalanine, 2;4;5-trihydroxy-phenylalanine, 3,4,5-trifluoro-D-phenylalanine, 3,4,5-trifluoro-L-phenylalanine, 3,4-dichloro-D-phenylalanine, 3,4-dichloro-L-phenylalanine, 3,4-difluoro-D-phenylalanine, 3,4-difluoro-L-phenylalanine, 3,4-dihydroxy-L-phenylalanine, 3,4-dimethoxy-L-phenylalanine, 3,5,3′-triiodo-L-thyronine, 3,5-diiodo-D-tyrosine, 3,5-diiodo-L-tyrosine, 3,5-diiodo-L-thyronine, 3-(trifluoromethyl)-D-phenylalanine, 3-(trifluoromethyl)-L-phenylalanine, 3-amino-L-tyrosine, 3-bromo-D-phenylalanine, 3-bromo-L-phenylalanine, 3-chloro-D-phenylalanine, 3-chloro-L-phenylalanine, 3-chloro-L-tyrosine, 3-cyano-D-phenylalanine, 3-cyano-L-phenylalanine, 3-fluoro-D-phenylalanine, 3-fluoro-L-phenylalanine, 3-fluoro-tyrosine, 3-iodo-D-phenylalanine, 3-iodo-L-phenylalanine, 3-iodo-L-tyrosine, 3-methoxy-L-tyrosine, 3-methyl-D-phenylalanine, 3-methyl-L-phenylalanine, 3-nitro-D-phenylalanine, 3-nitro-L-phenylalanine, 3-nitro-L-tyrosine, 4-(trifluoromethyl)-D-phenylalanine, 4-(trifluoromethyl)-L-phenylalanine, 4-amino-D-phenylalanine, 4-amino-L-phenylalanine, 4-benzoyl-D-phenylalanine, 4-benzoyl-L-phenylalanine, 4-bis(2-chloroethyl)amino-L-phenylalanine, 4-bromo-D-phenylalanine, 4-bromo-L-phenylalanine, 4-chloro-D-phenylalanine, 4-chloro-L-phenylalanine, 4-cyano-D-phenylalanine, 4-cyano-L-phenylalanine, 4-fluoro-D-phenylalanine, 4-fluoro-L-phenylalanine, 4-iodo-D-phenylalanine, 4-iodo-L-phenylalanine, homophenylalanine, thyroxine, 3,3-diphenylalanine, thyronine, ethyl-tyrosine, and methyl-tyrosine. 
     Amino acid analogs include analogs of proline. Examples of amino acid analogs of proline include, but are not limited to, 3,4-dehydro-proline, 4-fluoro-proline, cis-4-hydroxy-proline, thiazolidine-2-carboxylic acid, and trans-4-fluoro-proline. 
     Amino acid analogs include analogs of serine and threonine. Examples of amino acid analogs of serine and threonine include, but are not limited to, 3-amino-2-hydroxy-5-methylhexanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-ethoxybutanoic acid, 2-amino-3-methoxybutanoic acid, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-amino-3-benzyloxypropionic acid, 2-amino-3-benzyloxypropionic acid, 2-amino-3-ethoxypropionic acid, 4-amino-3-hydroxybutanoic acid, and α-methylserine. 
     Amino acid analogs include analogs of tryptophan. Examples of amino acid analogs of tryptophan include, but are not limited to, the following: α-methyl-tryptophan; β-(3-benzothienyl)-D-alanine; β-(3-benzothienyl)-L-alanine; 1-methyl-tryptophan; 4-methyl-tryptophan; 5-benzyloxy-tryptophan; 5-bromo-tryptophan; 5-chloro-tryptophan; 5-fluoro-tryptophan; 5-hydroxy-tryptophan; 5-hydroxy-L-tryptophan; 5-methoxy-tryptophan; 5-methoxy-L-tryptophan; 5-methyl-tryptophan; 6-bromo-tryptophan; 6-chloro-D-tryptophan; 6-chloro-tryptophan; 6-fluoro-tryptophan; 6-methyl-tryptophan; 7-benzyloxy-tryptophan; 7-bromo-tryptophan; 7-methyl-tryptophan; D-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 6-methoxy-1,2,3,4-tetrahydronorharman-l-carboxylic acid; 7-azatryptophan; L-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 5-methoxy-2-methyl-tryptophan; and 6-chloro-L-tryptophan. 
     In some embodiments, amino acid analogs are racemic. In some embodiments, the D isomer of the amino acid analog is used. In some embodiments, the L isomer of the amino acid analog is used. In other embodiments, the amino acid analog comprises chiral centers that are in the R or S configuration. In still other embodiments, the amino group(s) of a β-amino acid analog is substituted with a protecting group, e.g., tert-butyloxycarbonyl (BOC group), 9-fluorenylmethyloxycarbonyl (FMOC), tosyl, and the like. In yet other embodiments, the carboxylic acid functional group of a β-amino acid analog is protected, e.g., as its ester derivative. In some embodiments the salt of the amino acid analog is used. 
     A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequence of a polypeptide without abolishing or substantially abolishing its essential biological or biochemical activity (e.g., receptor binding or activation). An “essential” amino acid residue is a residue that, when altered from the wild-type sequence of the polypeptide, results in abolishing or substantially abolishing the polypeptide&#39;s essential biological or biochemical activity. 
     A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., K, R, H), acidic side chains (e.g., D, E), uncharged polar side chains (e.g., G, N, Q, S, T, Y, C), nonpolar side chains (e.g., A, V, L, I, P, F, M, W), beta-branched side chains (e.g., T, V, I) and aromatic side chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino acid residue in a polypeptide, e.g., is replaced with another amino acid residue from the same side chain family. Other examples of acceptable substitutions are substitutions based on isosteric considerations (e.g., norleucine for methionine) or other properties (e.g., 2-thienylalanine for phenylalanine, or 6-Cl-tryptophan for tryptophan). 
     The term “capping group” refers to the chemical moiety occurring at either the carboxy or amino terminus of the polypeptide chain of the subject peptidomimetic macrocycle. The capping group of a carboxy terminus includes an unmodified carboxylic acid (i.e. —COOH) or a carboxylic acid with a substituent. For example, the carboxy terminus can be substituted with an amino group to yield a carboxamide at the C-terminus. Various substituents include but are not limited to primary, secondary, and tertiary amines, including pegylated secondary amines. Representative secondary amine capping groups for the C-terminus include: 
     
       
         
         
             
             
         
       
     
     The capping group of an amino terminus includes an unmodified amine (i.e. —NH 2 ) or an amine with a substituent. For example, the amino terminus can be substituted with an acyl group to yield a carboxamide at the N-terminus. Various substituents include but are not limited to substituted acyl groups, including C 1 -C 6  carbonyls, C 7 -C 30  carbonyls, and pegylated carbamates. Representative capping groups for the N-terminus include, but are not limited to, 4-FBzl (4-fluoro-benzyl) and the following: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The term “member” as used herein in conjunction with macrocycles or macrocycle-forming linkers refers to the atoms that form or can form the macrocycle, and excludes substituent or side chain atoms. By analogy, cyclodecane, 1,2-difluoro-decane and 1,3-dimethyl cyclodecane are all considered ten-membered macrocycles as the hydrogen or fluoro substituents or methyl side chains do not participate in forming the macrocycle. 
     The symbol “ ” when used as part of a molecular structure refers to a single bond or a trans or cis double bond. 
     The term “amino acid side chain” refers to a moiety attached to the α-carbon (or another backbone atom) in an amino acid. For example, the amino acid side chain for alanine is methyl, the amino acid side chain for phenylalanine is phenylmethyl, the amino acid side chain for cysteine is thiomethyl, the amino acid side chain for aspartate is carboxymethyl, the amino acid side chain for tyrosine is 4-hydroxyphenylmethyl, etc. Other non-naturally occurring amino acid side chains are also included, for example, those that occur in nature (e.g., an amino acid metabolite) or those that are made synthetically (e.g., an α,α di-substituted amino acid). 
     The term “α,α di-substituted amino” acid refers to a molecule or moiety containing both an amino group and a carboxyl group bound to a carbon (the α-carbon) that is attached to two natural or non-natural amino acid side chains. 
     The term “polypeptide” encompasses two or more naturally or non-naturally-occurring amino acids joined by a covalent bond (e.g., an amide bond). Polypeptides as described herein include full-length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally-occurring proteins or synthetic polypeptide fragments). 
     The term “first C-terminal amino acid” refers to the amino acid which is closest to the C-terminus. The term “second C-terminal amino acid” refers to the amino acid attached at the N-terminus of the first C-terminal amino acid. 
     The term “macrocyclization reagent” or “macrocycle-forming reagent” as used herein refers to any reagent which can be used to prepare a peptidomimetic macrocycle by mediating the reaction between two reactive groups. Reactive groups can be, for example, an azide and alkyne, in which case macrocyclization reagents include, without limitation, Cu reagents such as reagents which provide a reactive Cu(I) species, such as CuBr, CuI or CuOTf, as well as Cu(II) salts such as Cu(CO 2 CH 3 ) 2 , CuSO 4 , and CuCl 2  that can be converted in situ to an active Cu(I) reagent by the addition of a reducing agent such as ascorbic acid or sodium ascorbate. Macrocyclization reagents can additionally include, for example, Ru reagents known in the art such as Cp*RuCl(PPh 3 ) 2 , [Cp*RuCl] 4  or other Ru reagents which can provide a reactive Ru(II) species. In other cases, the reactive groups are terminal olefins. In such embodiments, the macrocyclization reagents or macrocycle-forming reagents are metathesis catalysts including, but not limited to, stabilized, late transition metal carbene complex catalysts such as Group VIII transition metal carbene catalysts. For example, such catalysts are Ru and Os metal centers having a +2 oxidation state, an electron count of 16 and pentacoordinated. In other examples, catalysts have W or Mo centers. Various catalysts are disclosed in Grubbs et al., Acc. Chem. Res. 1995, 28, 446-452, U.S. Pat. No. 5,811,515; U.S. Pat. No. 7,932,397; U.S. Application No. 2011/0065915; U.S. Application No. 2011/0245477; Yu et al., Nature 2011, 479, 88; and Peryshkov et al., J. Am. Chem. Soc. 2011, 133, 20754. In yet other cases, the reactive groups are thiol groups. In such embodiments, the macrocyclization reagent is, for example, a linker functionalized with two thiol-reactive groups such as halogen groups. 
     The term “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine or a radical thereof. 
     The term “alkyl” refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1 -C 10  indicates that the group has from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it. 
     The term “alkylene” refers to a divalent alkyl (i.e., —R—). 
     The term “alkenyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2 -C 10  indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkenyl” refers to a C 2 -C 6  alkenyl chain. In the absence of any numerical designation, “alkenyl” is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it. 
     The term “alkynyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2 -C 10  indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkynyl” refers to a C 2 -C 6  alkynyl chain. In the absence of any numerical designation, “alkynyl” is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it. 
     The term “aryl” refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term “arylalkoxy” refers to an alkoxy substituted with aryl. 
     “Arylalkyl” refers to an aryl group, as defined above, wherein one of the aryl group&#39;s hydrogen atoms has been replaced with a C 1 -C 5  alkyl group, as defined above. Representative examples of an arylalkyl group include, but are not limited to, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4-pentylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t-butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl. 
     “Arylamido” refers to an aryl group, as defined above, wherein one of the aryl group&#39;s hydrogen atoms has been replaced with one or more —C(O)NH 2  groups. Representative examples of an arylamido group include 2-C(O)NH 2 -phenyl, 3-C(O)NH 2 -phenyl, 4-C(O)NH 2 -phenyl, 2-C(O)NH 2 -pyridyl, 3-C(O)NH 2 -pyridyl, and 4-C(O)NH 2 -pyridyl, 
     “Alkylheterocycle” refers to a C 1 -C 5  alkyl group, as defined above, wherein one of the C 1 -C 5  alkyl group&#39;s hydrogen atoms has been replaced with a heterocycle. Representative examples of an alkylheterocycle group include, but are not limited to, —CH 2 CH 2 -morpholine, —CH 2 CH 2 -piperidine, —CH 2 CH 2 CH 2 -morpholine, and —CH 2 CH 2 CH 2 -imidazole. 
     “Alkylamido” refers to a C 1 -C 5  alkyl group, as defined above, wherein one of the C 1 -C 5  alkyl group&#39;s hydrogen atoms has been replaced with a —C(O)NH 2  group. Representative examples of an alkylamido group include, but are not limited to, —CH 2 —C(O)NH 2 , —CH 2 CH 2 —C(O)NH 2 , —CH 2 CH 2 CH 2 C(O)NH 2 , —CH 2 CH 2 CH 2 CH 2 C(O)NH 2 , —CH 2 CH 2 CH 2 CH 2 CH 2 C(O)NH 2 , —CH 2 CH(C(O)NH 2 )CH 3 , —CH 2 CH(C(O)NH 2 )CH 2 CH 3 , —CH(C(O)NH 2 )CH 2 CH 3 , —C(CH 3 ) 2 CH 2 C(O)NH 2 , —CH 2 —CH 2 —NH—C(O)—CH 3 , —CH 2 —CH 2 —NH—C(O)—CH 3 —CH3, and —CH 2 —CH 2 —NH—C(O)—CH═CH 2 . 
     “Alkanol” refers to a C 1 -C 5  alkyl group, as defined above, wherein one of the C 1 -C 5  alkyl group&#39;s hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 CH 3 , —CH(OH)CH 3  and —C(CH 3 ) 2 CH 2 OH. 
     “Alkylcarboxy” refers to a C 1 -C 5  alkyl group, as defined above, wherein one of the C 1 -C 5  alkyl group&#39;s hydrogen atoms has been replaced with a —COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, —CH 2 COOH, —CH 2 CH 2 COOH, —CH 2 CH 2 CH 2 COOH, —CH 2 CH 2 CH 2 CH 2 COOH, —CH 2 CH(COOH)CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 COOH, —CH 2 CH(COOH)CH 2 CH 3 , —CH(COOH)CH 2 CH 3  and —C(CH 3 ) 2 CH 2 COOH. 
     The term “cycloalkyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. 
     The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like. 
     The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl. 
     The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl. 
     The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. 
     The term “substituent” refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound, or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups. 
     In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are included unless expressly provided otherwise. In some embodiments, the compounds disclosed herein are also represented in multiple tautomeric forms, in such instances, the compounds include all tautomeric forms of the compounds described herein (e.g., if alkylation of a ring system results in alkylation at multiple sites, the invention includes all such reaction products). All such isomeric forms of such compounds are included unless expressly provided otherwise. All crystal forms of the compounds described herein are included unless expressly provided otherwise. 
     As used herein, the terms “increase” and “decrease” mean, respectively, to cause a statistically significantly (i.e., p&lt;0.1) increase or decrease of at least 5%. 
     As used herein, the recitation of a numerical range for a variable is intended to convey that the variable is equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, or any other real values≧0 and ≦2 if the variable is inherently continuous. 
     As used herein, unless specifically indicated otherwise, the word “or” is used in the inclusive sense of “and/or” and not the exclusive sense of “either/or.” 
     The term “on average” represents the mean value derived from performing at least three independent replicates for each data point. 
     The term “biological activity” encompasses structural and functional properties of a macrocycle. Biological activity is, for example, structural stability, alpha-helicity, affinity for a target, resistance to proteolytic degradation, cell penetrability, intracellular stability, in vivo stability, or any combination thereof. 
     The term “binding affinity” refers to the strength of a binding interaction, for example between a peptidomimetic macrocycle and a target. Binding affinity can be expressed, for example, as an equilibrium dissociation constant (“K d ”), which is expressed in units which are a measure of concentration (e.g. M, mM, μM, nM etc). Numerically, binding affinity and K d  values vary inversely, such that a lower binding affinity corresponds to a higher K d  value, while a higher binding affinity corresponds to a lower K d  value. Where high binding affinity is desirable, “improved” binding affinity refers to higher binding affinity and therefore lower K d  values. 
     In some embodiments, the compounds of the invention can have K d  values of about 0.05 μM to 1000 nM. In some embodiments, the compounds of the invention can have K d  values of about 0.5 μM to 1 μM. In some embodiments, the compounds of the invention can have K d  values of about 20 μM to 100 μM. In some embodiments, the compounds of the invention can have K d  values of about 500 μM to 1 nM. In some embodiments, the compounds of the invention can have K d  values of about 50 nM to 100 nM. In some embodiments, the compounds of the invention can have K d  values of about 500 nM to 1000 nM. 
     The term “in vitro efficacy” refers to the extent to which a test compound, such as a peptidomimetic macrocycle, produces a beneficial result in an in vitro test system or assay. In vitro efficacy can be measured, for example, as an “IC 50 ” or “EC 50 ” value, which represents the concentration of the test compound which produces 50% of the maximal effect in the test system. 
     The term “ratio of in vitro efficacies” or “in vitro efficacy ratio” refers to the ratio of IC 50  or EC 50  values from a first assay (the numerator) versus a second assay (the denominator). Consequently, an improved in vitro efficacy ratio for Assay 1 versus Assay 2 refers to a lower value for the ratio expressed as IC 50 (Assay 1)/IC 50 (Assay 2) or alternatively as EC 50 (Assay 1)/EC 50 (Assay 2). This concept can also be characterized as “improved selectivity” in Assay 1 versus Assay 2, which can be due either to a decrease in the IC 50  or EC 50  value for Target 1 or an increase in the value for the IC 50  or EC 50  value for Target 2. 
     In some embodiments, the compounds of the invention can have IC 50  values of about 0.05 μM to 1000 nM. In some embodiments, the compounds of the invention can have IC 50  values of about 0.5 μM to 1 μM. In some embodiments, the compounds of the invention can have IC 50  values of about 20 μM to 100 μM. In some embodiments, the compounds of the invention can have IC 50  values of about 500 μM to 1 nM. In some embodiments, the compounds of the invention can have IC 50  values of about 50 nM to 100 nM. In some embodiments, the compounds of the invention can have IC 50  values of about 500 nM to 1000 nM. 
     In some embodiments, the compounds of the invention can have EC 50  values of about 0.05 μM to 1000 nM. In some embodiments, the compounds of the invention can have EC 50  values of about 0.5 μM to 1 μM. In some embodiments, the compounds of the invention can have EC 50  values of about 20 μM to 100 μM. In some embodiments, the compounds of the invention can have EC 50  values of about 500 μM to 1 nM. In some embodiments, the compounds of the invention can have EC 50  values of about 50 nM to 100 nM. In some embodiments, the compounds of the invention can have EC 50  values of about 500 nM to 1000 nM. 
     In certain embodiments, the human subject is refractory and/or intolerant to one or more other standard treatment of the infectious disease known in art. In some embodiments, the human subject has had at least one unsuccessful prior treatment and/or therapy of the infectious disease. 
     In some embodiments, a subject treated for an infectious disease in accordance with the methods provided herein is a human, who has or is diagnosed with an infectious disease. In other embodiments, a subject treated for an infectious disease in accordance with the methods provided herein is a human, predisposed or susceptible to an infectious disease. In some embodiments, a subject treated for an infectious disease in accordance with the methods provided herein is a human, at risk of developing an infectious disease. 
     The details of one or more particular embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 
     Pharmaceutically-Acceptable Salts 
     The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. 
     Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. 
     In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. 
     Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. 
     In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. 
     Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. 
     In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt , or a maleate salt. 
     Purity of Compounds of the Invention 
     Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. 
     Formulation and Administration 
     Mode of Administration 
     An effective amount of a peptidomimetic macrocycles of the disclosure can be administered in either single or multiple doses by any of the accepted modes of administration. In some embodiments, the peptidomimetic macrocycles of the disclosure are administered parenterally, for example, by subcutaneous, intramuscular, intrathecal, intravenous or epidural injection. For example, the peptidomimetic macrocycle is administered intravenously, intraarterially, subcutaneously or by infusion. In some examples, the peptidomimetic macrocycle is administered intravenously. In some examples, the peptidomimetic macrocycle is administered intraarterially. 
     Regardless of the route of administration selected, the peptidomimetic macrocycles of the present disclosure, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms. The peptidomimetic macrocycles according to the disclosure can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals. 
     In one aspect, the disclosure provides pharmaceutical formulation comprising a therapeutically-effective amount of one or more of the peptidomimetic macrocycles described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. In one embodiment, one or more of the peptidomimetic macrocycles described herein are formulated for parenteral administration for parenteral administration, one or more peptidomimetic macrocycles disclosed herein can be formulated as aqueous or nonaqueous solutions, dispersions, suspensionsor emulsions or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use. Such formulations can comprise sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. If desired the formulation can be diluted prior to use with, for example, an isotonic saline solution or a dextrose solution. In some examples, the peptidomimetic macrocycle is formulated as an aqueous solution and is administered intravenously. 
     Amount and frequency of administration 
     Dosing can be determined using various techniques. The selected dosage level can depend upon a variety of factors including the activity of the particular peptidomimetic macrocycle employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular peptidomimetic macrocycle being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular peptidomimetic macrocycle employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The dosage values can also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. 
     A physician or veterinarian can prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 
     In some embodiments, a suitable daily dose of a peptidomimetic macrocycle of the disclosure can be that amount of the peptidomimetic macrocycle which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. The precise time of administration and amount of any particular peptidomimetic macrocycle that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular peptidomimetic macrocycle, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like. 
     Dosage can be based on the amount of the peptidomimetic macrocycle per kg body weight of the patient. Alternatively, the dosage of the subject disclosure can be determined by reference to the plasma concentrations of the peptidomimetic macrocycle. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity (AUC) can be used. 
     In some embodiments, the subject is a human subject and the amount of the peptidomimetic macrocycle administered is 0.01-100 mg per kilogram body weight of the human subject. For example, in various examples, the amount of the peptidomimetic macrocycle administered is about 0.01-50 mg/kg, about 0.01-20 mg/kg, about 0.01-10 mg/kg, about 0.1-100 mg/kg, about 0.1-50 mg/kg, about 0.1-20 mg/kg, about 0.1-10 mg/kg, about 0.5-100 mg/kg, about 0.5-50 mg/kg, about 0.5-20 mg/kg, about 0.5-10 mg/kg, about 1-100 mg/kg, about 1-50 mg/kg, about 1-20 mg/kg, about 1-10 mg/kg body weight of the human subject. In one embodiment, about 0.5 mg-10 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered. In some examples the amount of the peptidomimetic macrocycle administered is about 0.16 mg, about 0.32 mg, about 0.64 mg, about 1.28 mg, about 3.56 mg, about 7.12 mg, about 14.24 mg, or about 20 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 0.16 mg, about 0.32 mg, about 0.64 mg, about 1.28 mg, about 3.56 mg, about 7.12 mg, or about 14.24 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 0.16 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 0.32 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 0.64 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 1.28 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 3.56 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 7.12 mg per kilogram body weight of the human subject. In some examples the amount of the peptidomimetic macrocycle administered is about 14.24 mg per kilogram body weight of the human subject. 
     In some embodiments about 0.5- about 20 mg or about 0.5- about 10 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered two times a week. For example about 0.5- about 1 mg, about 0.5- about 5 mg, about 0.5- about 10 mg, about 0.5- about 15 mg, about 1- about 5 mg, about 1- about 10 mg, about 1- about 15 mg, about 1- about 20 mg, about 5- about 10 mg, about 1- about 15 mg, about 5- about 20 mg, about 10- about 15 mg, about 10- about 20 mg, or about 15- about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered about twice a week. In some examples about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered two times a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 20 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered two times a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg or about 10 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered two times a week. 
     In some embodiments about 0.5- about 20 mg or about 0.5- about 10 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered once a week. For example about 0.5- about 1 mg, about 0.5- about 5 mg, about 0.5- about 10 mg, about 0.5- about 15 mg, about 1- about 5 mg, about 1- about 10 mg, about 1- about 15 mg, about 1- about 20 mg, about 5- about 10 mg, about 1- about 15 mg, about 5- about 20 mg, about 10- about 15 mg, about 10- about 20 mg, or about 15- about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered once a week. In some examples about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered once a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 20 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg or about 10 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once a week. 
     In some embodiments about 0.5- about 20 mg or about 0.5- about 10 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered 3, 4, 5, 6, or 7 times a week. For example, about 0.5- about 1 mg, about 0.5- about 5 mg, about 0.5- about 10 mg, about 0.5- about 15 mg, about 1- about 5 mg, about 1- about 10 mg, about 1- about 15 mg, about 1- about 20 mg, about 5- about 10 mg, about 1- about 15 mg, about 5- about 20 mg, about 10- about 15 mg, about 10- about 20 mg, or about 15- about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered 3, 4, 5, 6, or 7 times a week. In some examples about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered 3, 4, 5, 6, or 7 times a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 20 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered 3, 4, 5, 6, or 7 times a week. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, or about 10 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered 3, 4, 5, 6, or 7 times a week. 
     In some embodiments, about 0.5- about 20 mg or about 0.5- about 10 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered once every 2, 3, or 4 weeks. For example, about 0.5- about 1 mg, about 0.5- about 5 mg, about 0.5- about 10 mg, about 0.5- about 15 mg, about 1- about 5 mg, about 1- about 10 mg, about 1- about 15 mg, about 1- about 20 mg, about 5- about 10 mg, about 1- about 15 mg, about 5- about 20 mg, about 10- about 15 mg, about 10- about 20 mg, or about 15- about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administrated 3, 4, 5, 6, or 7 once every 2 or 3 week. In some examples about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg of the peptidomimetic macrocycle per kilogram body weight of the human subject is administered once every 2 or 3 weeks. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 20 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once every 2 weeks. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg or about 10 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once every 2 weeks. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 20 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once every 3 weeks. In some examples, the amount of the peptidomimetic macrocycle administered is about 1.25 mg, about 2.5 mg, about 5 mg, or about 10 mg per kilogram body weight of the human subject and the peptidomimetic macrocycle is administered once every 3 weeks. 
     In some embodiments, the peptidomimetic macrocycle is administered gradually over a period of time. A desired amount of peptidomimetic macrocycle can, for example can be administered gradually over a period of from about 0.1 h -24 h. In some cases a desired amount of peptidomimetic macrocycle is administered gradually over a period of 0.1 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, or 24 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 0.25-12 h, for example over a period of 0.25-1 h, 0.25-2 h, 0.25-3 h, 0.25-4 h, 0.25-6 h, 0.25-8 h, 0.25-10 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 0.25-2 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 0.25-1 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 0.25 h, 0.3 h, 0.4 h, 0.5 h, 0.6 h, 0.7 h, 0.8 h, 0.9 h, 1.0 h, 1.1 h, 1.2 h, 1.3 h, 1.4 h, 1.5 h, 1.6 h, 1.7 h, 1.8 h, 1.9 h, or 2.0 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 1 h. In some examples, a desired amount of peptidomimetic macrocycle is administered gradually over a period of 2 h. 
     Administration of the peptidomimetic macrocycles can continue as long as necessary. In some embodiments, one or more peptidomimetic macrocycle of the disclosure is administered for more than 1 day, more than 1 week, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than 12 months, more than 13 months, more than 14 months, more than 15 months, more than 16 months, more than 17 months, more than 18 months, more than 19 months, more than 20 months, more than 21 months, more than 22 months, more than 23 months, or more than 24 months. In some embodiments, one or more peptidomimetic macrocycle of the disclosure is administered for less than 1 week, less than 1 month, less than 2 months, less than 3 months, less than 4 months, less than 5 months, less than 6 months, less than 7 months, less than 8 months, less than 9 months, less than 10 months, less than 11 months, less than 12 months, less than 13 months, less than 14 months, less than 15 months, less than 16 months, less than 17 months, less than 18 months, less than 19 months, less than 20 months, less than 21 months, less than 22 months, less than 23 months, or less than 24 months. 
     In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 15 and 28 of a 28 day cycle. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 15 and 28 of a 28 day cycle and administration is continued for two cycles. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 15 and 28 of a 28 day cycle and administration is continued for three cycles. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 15 and 28 of a 28 day cycle and administration is continued for 4, 5, 6, 7, 8, 9, 10, or more cycles. 
     In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 11 and 21 of a 21-day cycle. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 11 and 21 of a 21-day cycle and administration is continued for two cycles. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 11 and 21 of a 21-day cycle and administration is continued for three cycles. In some embodiments, the peptidomimetic macrocycle is administered on day 1, 8, 11 and 21 of a 21-day cycle and administration is continued for 4, 5, 6, 7, 8, 9, 10, or more cycles. 
     In some embodiments, one or more peptidomimetic macrocycle of the disclosure is administered chronically on an ongoing basis. In some embodiments administration of one or more peptidomimetic macrocycle of the disclosure is continued until documentation of disease progression, unacceptable toxicity, or patient or physician decision to discontinue administration. 
     In some embodiments, the compounds of the invention can be used to treat one condition. In some embodiments, the compounds of the invention can be used to treat two conditions. In some embodiments, the compounds of the invention can be used to treat three conditions. In some embodiments, the compounds of the invention can be used to treat four conditions. In some embodiments, the compounds of the invention can be used to treat five conditions. 
     Sequence Homology 
     Two or more peptides can share a degree of homology. A pair of peptides can have, for example, up to about 20% pairwise homology, up to about 25% pairwise homology, up to about 30% pairwise homology, up to about 35% pairwise homology, up to about 40% pairwise homology, up to about 45% pairwise homology, up to about 50% pairwise homology, up to about 55% pairwise homology, up to about 60% pairwise homology, up to about 65% pairwise homology, up to about 70% pairwise homology, up to about 75% pairwise homology, up to about 80% pairwise homology, up to about 85% pairwise homology, up to about 90% pairwise homology, up to about 95% pairwise homology, up to about 96% pairwise homology, up to about 97% pairwise homology, up to about 98% pairwise homology, up to about 99% pairwise homology, up to about 99.5% pairwise homology, or up to about 99.9% pairwise homology. A pair of peptides can have, for example, at least about 20% pairwise homology, at least about 25% pairwise homology, at least about 30% pairwise homology, at least about 35% pairwise homology, at least about 40% pairwise homology, at least about 45% pairwise homology, at least about 50% pairwise homology, at least about 55% pairwise homology, at least about 60% pairwise homology, at least about 65% pairwise homology, at least about 70% pairwise homology, at least about 75% pairwise homology, at least about 80% pairwise homology, at least about 85% pairwise homology, at least about 90% pairwise homology, at least about 95% pairwise homology, at least about 96% pairwise homology, at least about 97% pairwise homology, at least about 98% pairwise homology, at least about 99% pairwise homology, at least about 99.5% pairwise homology, at least about 99.9% pairwise homology. 
     Various methods and software programs can be used to determine the homology between two or more peptides, such as NCBI BLAST, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, or another suitable method or algorithm. 
     Overview 
     The outer membrane (OM) of Gram-negative bacteria (GNB) contains lipopolysaccharide (LPS), which can contribute to the structural integrity of the bacteria and can protect the bacteria from harsh environments and toxic compounds, including antibiotics. LPS is synthesized at the inner membrane and is translocated to the OM via a complex of proteins known as Lpt A-G.  FIG. 1  depicts the transport of LPS to the OM via the formation of an LptD-LptE complex. 
     LptD is an outer-membrane protein widely distributed in GNB that functions in the assembly of LPS in the outer leaflet of the OM. LptD can form a complex with LptE and the resulting LptD-LptE complex plays an important role in the correct insertion of LPS into the OM. Disruption of the LptD-LptE complex renders the bacteria unable to translocate LPS into the OM and compromises the integrity of the OM. Peptidomimetic antibiotics with β-hairpin secondary structures can be used to target LptD in bacteria, such as  P. aeruginosa  and  E. coli.    
     An X-ray structure of an LptD-LptE complex reveals a two-protein barrel and plug architecture, wherein LptD forms a 26-stranded β-barrel and LptE adopts a roll-like structure inside the barrel.  FIG. 2  illustrates the barrel and plug architecture of an LptD-LptE complex. A combined β-strand and α-helical domain of LptE contacts the inner pore of the β-barrel formed by LptD.  FIG. 3  illustrates the potential hydrophobic residues of LptE for LPS binding. Residues involved in LptD/LptE interactions are circled. 
     Peptidomimetic macrocycles (e.g., β-hairpins) disclosued herein can be used to disrupt the LPS transport function of LptD. For example, the peptidomimetic macrocycles can disrupt the formation of LptD-LptE complexes and lead to the disruption of the OM of GNB. The peptidomimetic macrocycles (e.g., β-hairpins) disclosed herein can mimic the interacting domain of LptE. These peptidomimetic macrocycles can compete with and thus block the function of LptD-LptE complexes. In some embodiments, the peptidomimetic macrocycles disclosed herein, such as those with β-hairpins, can be used as antibiotics to target LptD. In some embodiments, the peptidomimetic macrocycles can impair the outer-membrane permeability barrier during bacterial growth. In some embodiments, the peptidomimetic macrocycles can interfere with the function of LptD and can also allow the entry of phospholipids into the outer leaflet of the OM. 
     Treatment of a Disorder 
     Disorders that can be treated by the compositions, formulations, and/or methods described herein include, but are not limited to, infectious diseases. Infectious diseases can be caused by pathogens, such as bacteria, viruses, fungi or parasites. In some embodiments, an infectious disease can be passed from person to person. In some embodiments, an infectious disease can be transmitted by bites from insects or animals. In some embodiments, an infectious disease can be acquired by ingesting contaminated food or water or being exposed to organisms in the environment. Some infectious diseases can be prevented by vaccines. 
     In specific embodiments, infectious diseases that can be treated by the compositions, formulations, and/or methods described herein include, but are not limited to,  Acinetobacter  infections, Actinomycosis, African sleeping sickness (African trypanosomiasis), AIDS (Acquired immunodeficiency syndrome), Amebiasis, Anaplasmosis, Angiostrongyliasis, Anisakiasis, Anthrax, Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever, Ascariasis, Aspergillosis, Astrovirus infection, Babesiosis,  Bacillus cereus  infection, Bacterial pneumonia, Bacterial vaginosis, Bacteroides infection, Balantidiasis, Bartonellosis, Baylisascaris infection, BK virus infection, Black piedra, Blastocystosis, Blastomycosis, Bolivian hemorrhagic fever, Botulism (and Infant botulism), Brazilian hemorrhagic fever, Brucellosis, Bubonic plague,  Burkholderia  infection, Buruli ulcer, Calicivirus infection (Norovirus and Sapovirus), Campylobacteriosis, Candidiasis (Moniliasis; Thrush), Capillariasis, Carrion&#39;s disease, Cat-scratch disease, Cellulitis, Chagas Disease (American trypanosomiasis), Chancroid, Chickenpox, Chikungunya, Chlamydia, Chlamydophila pneumoniae infection (Taiwan acute respiratory agent or TWAR), Cholera, Chromoblastomycosis, Chytridiomycosis, Clonorchiasis,  Clostridium difficile  colitis, Coccidioidomycosis, Colorado tick fever (CTF), Common cold (Acute viral rhinopharyngitis; Acute coryza), Creutzfeldt-Jakob disease (CJD), Crimean-Congo hemorrhagic fever (CCHF), Cryptococcosis, Cryptosporidiosis, Cutaneous larva migrans (CLM), Cyclosporiasis, Cysticercosis, Cytomegalovirus infection, Dengue fever, Desmodesmus infection, Dientamoebiasis, Diphtheria, Diphyllobothriasis, Dracunculiasis, Ebola hemorrhagic fever, Echinococcosis, Ehrlichiosis, Enterobiasis (Pinworm infection),  Enterococcus  infection, Enterovirus infection, Epidemic typhus, Erythema infectiosum (Fifth disease), Exanthem subitum (Sixth disease), Fasciolasis, Fasciolopsiasis, Fatal familial insomnia (FFI), Filariasis, Food poisoning by  Clostridium perfringens,  Free-living amebic infection, Fusobacterium infection, Gas gangrene (Clostridial myonecrosis), Geotrichosis, Gerstmann-Sträussler-Scheinker syndrome (GSS), Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Granuloma inguinale (Donovanosis), Group A streptococcal infection, Group B streptococcal infection, Haemophilus influenzae infection, Hand, foot and mouth disease (HFMD), Hantavirus Pulmonary Syndrome (HPS), Heartland virus disease,  Helicobacter pylori  infection, Hemolytic-uremic syndrome (HUS), Hemorrhagic fever with renal syndrome (HFRS), Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpes simplex, Histoplasmosis, Hookworm infection, Human bocavirus infection, Human ewingii ehrlichiosis, Human granulocytic anaplasmosis (HGA), Human metapneumovirus infection, Human monocytic ehrlichiosis, Human papillomavirus (HPV) infection, Human parainfluenza virus infection, Hymenolepiasis, Epstein-Barr Virus Infectious Mononucleosis (Mono), Influenza (flu), Isosporiasis, Kawasaki disease, Keratitis, Kingella kingae infection, Kuru, Lassa fever, Legionellosis (Legionnaires&#39; disease), Legionellosis (Pontiac fever), Leishmaniasis, Leprosy, Leptospirosis, Listeriosis, Lyme disease (Lyme borreliosis), Lymphatic filariasis (Elephantiasis), Lymphocytic choriomeningitis, Malaria, Marburg hemorrhagic fever (MHF), Measles, Middle East respiratory syndrome (MERS), Melioidosis (Whitmore&#39;s disease), Meningitis, Meningococcal disease, Metagonimiasis, Microsporidiosis, Molluscum contagiosum (MC), Monkeypox, Mumps, Murine typhus (Endemic typhus), Mycoplasma pneumonia, Mycetoma (disambiguation), Myiasis, Neonatal conjunctivitis (Ophthalmia neonatorum), Variant Creutzfeldt-Jakob disease (vCJD, nvCJD), Nocardiosis, Onchocerciasis (River blindness), Opisthorchiasis, Paracoccidioidomycosis (South American blastomycosis), Paragonimiasis, Pasteurellosis, Pediculosis capitis (Head lice), Pediculosis corporis (Body lice), Pediculosis pubis (Pubic lice, Crab lice), Pelvic inflammatory disease (PID), Pertussis (Whooping cough), Plague, Pneumococcal infection, Pneumocystis pneumonia (PCP), Pneumonia, Poliomyelitis, Prevotella infection, Primary amoebic meningoencephalitis (PAM), Progressive multifocal leukoencephalopathy, Psittacosis, Q fever, Rabies, Relapsing fever, Respiratory syncytial virus infection, Rhinosporidiosis, Rhinovirus infection, Rickettsial infection, Rickettsialpox, Rift Valley fever (RVF), Rocky Mountain spotted fever (RMSF), Rotavirus infection, Rubella, Salmonellosis, SARS (Severe Acute Respiratory Syndrome), Scabies, Schistosomiasis, Sepsis, Shigellosis (Bacillary dysentery), Shingles (Herpes zoster), Smallpox (Variola), Sporotrichosis, Staphylococcal food poisoning, Staphylococcal infection, Strongyloidiasis, Subacute sclerosing panencephalitis, Syphilis, Taeniasis, Tetanus (Lockjaw), Tinea barbae (Barber&#39;s itch), Tinea capitis (Ringworm of the Scalp), Tinea corporis (Ringworm of the Body), Tinea cruris (Jock itch), Tinea manum (Ringworm of the Hand), Tinea nigra, Tinea pedis (Athlete&#39;s foot), Tinea unguium (Onychomycosis), Tinea versicolor (Pityriasis versicolor), Toxocariasis (Ocular Larva Migrans (OLM)), Toxocariasis (Visceral Larva Migrans (VLM)), Trachoma, Toxoplasmosis, Trichinosis, Trichomoniasis, Trichuriasis (Whipworm infection), Tuberculosis, Tularemia, Typhoid fever, Typhus fever, Ureaplasma urealyticum infection, Valley fever, Venezuelan equine encephalitis, Venezuelan hemorrhagic fever, Vibrio vulnificus infection, Vibrio parahaemolyticus enteritis, Viral pneumonia, West Nile Fever, White piedra (Tinea blanca), Yersinia pseudotuberculosis infection, Yersiniosis, Yellow fever, and Zygomycosis. 
     The compositions, formulations, and/or methods described herein can be used to treat a pathogen. In some embodiments, the pathogen can be a virus, bacterium, prion, a fungus, or a parasite. In specific embodiments, the pathogen described herein include, but are not limited to,  Acinetobacter baumannii, Actinomyces israelii, Actinomyces gerencseriae  and  Propionibacterium propionicus, Trypanosoma brucei,  HIV (Human immunodeficiency virus),  Entamoeba histolytica, Anaplasma  species,  Angiostrongylus, Anisakis, Bacillus anthracis, Arcanobacterium haemolyticum,  Junin virus,  Ascaris lumbricoides, Aspergillus  species, Astroviridae family,  Babesia  species,  Bacillus cereus,  bacterial vaginosis microbiota,  Bacteroides  species,  Balantidium coli, Bartonella, Baylisascaris  species, BK virus,  Piedraia hortae, Blastocystis  species,  Blastomyces dermatitidis,  Machupo virus,  Clostridium botulinum, Sabia, Brucella  species,  Enterobacteriaceae, Burkholderia cepacia  and other  Burkholderia  species,  Mycobacterium ulcerans,  Caliciviridae family,  Campylobacter  species,  Candida albicans  and other  Candida  species,  Capillaria philippinensis, Capillaria hepatica, Capillaria aerophila, Bartonella bacilliformis, Bartonella henselae,  Group A  Streptococcus  and  Staphylococcus, Trypanosoma cruzi, Haemophilus ducreyi,  Varicella zoster virus (VZV), Alphavirus,  Chlamydia trachomatis, Chlamydophila pneumoniae, Vibrio cholera, Fonsecaea pedrosoi, Batrachochytrium dendrabatidis, Clonorchis sinensis, Clostridium difficile, Coccidioides immitis  and  Coccidioides posadasii,  Colorado tick fever virus (CTFV), rhinoviruses and coronaviruses, PRNP, Crimean-Congo hemorrhagic fever virus,  Cryptococcus neoformans, Cryptosporidium  species,  Ancylostoma braziliense;  multiple other parasites,  Cyclospora cayetanensis, Taenia solium, Cytomegalovirus,  Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4)—Flaviviruses, Green algae  Desmodesmus armatus, Dientamoeba fragilis, Corynebacterium diphtheria, Diphyllobothrium, Dracunculus medinensis,  Ebolavirus (EBOV),  Echinococcus  species,  Ehrlichia species, Enterobius vermicularis, Enterococcus  species,  Enterovirus  species,  Rickettsia prowazekii,  Parvovirus B19, Human herpesvirus 6 (HHV-6) and Human herpesvirus 7 (HHV-7),  Fasciola hepatica  and  Fasciola gigantica, Fasciolopsis buski,  PRNP, Filarioidea superfamily,  Clostridium perfringens, Fusobacterium  species,  Clostridium perfringens,  other  Clostridium  species,  Geotrichum candidum, Giardia lamblia, Burkholderia mallei, Gnathostoma spinigerum  and  Gnathostoma hispidum, Neisseria gonorrhoeae, Klebsiella granulomatis, Streptococcus pyogenes, Streptococcus agalactiae, Haemophilus influenza,  Enteroviruses, mainly Coxsackie A virus and Enterovirus 71 (EV71), Sin Nombre virus, Heartland virus,  Helicobacter pylori, Escherichia coli  O157:H7, O111 and O104:H4, Bunyaviridae family, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2),  Histoplasma capsulatum, Ancylostoma duodenale  and  Necator americanus,  Human bocavirus (HBoV),  Ehrlichia ewingii, Anaplasma phagocytophilum,  Human metapneumovirus (hMPV),  Ehrlichia chaffeensis,  Human papillomavirus (HPV), Human parainfluenza viruses (HPIV),  Hymenolepis nana  and  Hymenolepis diminuta,  Epstein-Barr Virus (EBV), Orthomyxoviridae family,  Isospora belli, Kingella kingae,  Lassa virus,  Legionella pneumophila, Leishmania  species,  Mycobacterium leprae, Mycobacterium lepromatosis, Leptospira  species,  Listeria monocytogenes, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, Wuchereria bancrofti, Brugia malayi,  Lymphocytic choriomeningitis virus (LCMV),  Plasmodium  species, Marburg virus, Measles virus, Middle East respiratory syndrome coronavirus,  Burkholderia pseudomallei, Neisseria meningitides, Metagonimus yokagawai, Microsporidia phylum,  Molluscum contagiosum virus (MCV), Monkeypox virus, Mumps virus,  Rickettsia typhi, Mycoplasma pneumoniae, Actinomycetoma, Eumycetoma,  parasitic dipterous fly larvae,  Chlamydia trachomatis, Neisseria gonorrhoeae, Nocardia asteroids, Nocardia  species,  Onchocerca volvulus, Opisthorchis viverrini  and  Opisthorchis felineus, Paracoccidioides brasiliensis, Pediculus humanus capitis, Phthirus pubis, Bordetella pertussis, Yersinia pestis, Streptococcus pneumoniae, Pneumocystis jirovecii, Poliovirus, Prevotella  species,  Naegleria fowleri,  JC virus,  Chlamydophila psittaci, Coxiella burnetii,  Rabies virus,  Borrelia hermsii, Borrelia recurrentis, Borrelia  species, Respiratory syncytial virus (RSV),  Rhinosporidium seeberi,  Rhinovirus,  Rickettsia  species,  Rickettsia akari,  Rift Valley fever virus,  Rickettsia rickettsia,  Rotavirus, Rubella virus,  Salmonella  species, SARS coronavirus,  Sarcoptes scabiei, Schistosoma  species,  Shigella  species, Varicella zoster virus (VZV),  Variola major, Variola minor, Sporothrix schenckii, Staphylococcus  species,  Strongyloides stercoralis,  Measles virus,  Treponema pallidum, Taenia  species,  Clostridium tetani, Trichophyton  species,  Trichophyton tonsurans, Epidermophyton floccosum, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton rubrum, Hortaea werneckii, Trichophyton  species,  Trichophyton  species,  Malassezia  species,  Toxocara canis, Toxocara cati, Chlamydia trachomatis, Toxoplasma gondii, Trichinella spiralis, Trichomonas vaginalis, Trichuris trichiura, Mycobacterium tuberculosis, Francisella tularensis, Salmonella enterica  subsp.  enterica, serovar typhi, Rickettsia, Ureaplasma urealyticum, Coccidioides immitis, Coccidioides posadasii,  Venezuelan equine encephalitis virus, Guanarito virus,  Vibrio vulnificus, Vibrio parahaemolyticus,  multiple viruses, West Nile virus,  Trichosporon beigelii, Yersinia pseudotuberculosis, Yersinia enterocolitica,  Yellow fever virus, Mucorales order (Mucormycosis), and Entomophthorales order (Entomophthoramycosis). 
     In some embodiments, the compounds of the invention can be toxic to one microbe. In some embodiments, the compounds of the invention can be toxic to two microbes. In some embodiments, the compounds of the invention can be toxic to three microbes. In some embodiments, the compounds of the invention can be toxic to four microbes. In some embodiments, the compounds of the invention can be toxic to five microbes. 
     In some embodiments, the compounds of the invention can be used to treat a microbe without damaging the host subject. In some embodiments, the compounds of the invention can be used to treat two microbes without damaging the host subject. In some embodiments, the compounds of the invention can be used to treat three microbes without damaging the host subject. In some embodiments, the compounds of the invention can be used to treat four microbes without damaging the host subject. In some embodiments, the compounds of the invention can be used to treat five microbes without damaging the host subject. 
     Peptidomimetic Macrocycles 
     In some embodiments, a peptidomimetic macrocycle has the Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
         each A, C, D, and E is independently an amino acid (including natural or non-natural amino acids, and amino acid analogs) and the terminal D and E independently optionally include a capping group;   each B is independently an amino acid (including natural or non-natural amino acids, and amino acid analogs),       

     
       
         
         
             
             
         
       
     
     [—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, unsubstituted or substituted with halo-;   R 3  is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R 5 ;   L is a macrocycle-forming linker of the formula -L 1 -L 2 -;   L 1  and L 2  and L 3  are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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, 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, aryl, or heteroaryl, 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, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;   v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;   u is an integer from 1-10, for example 1-5, 1-3 or 1-2;   x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and   n is an integer from 1-5.       

     In some embodiments, v and w are integers from 1-30. In some embodiments, w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10. In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6. 
     In some embodiments, w is an integer from 3-10, for example 3-6, 3-8, 6-8, or 6-10. In some embodiments, w is 3. In other embodiments, w is 6. In some embodiments, v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10. In some embodiments, v is 2. 
     In an embodiment of any of the Formulas described herein, L 1  and L 2 , either alone or in combination, do not form a triazole or a thioether. 
     In one example, at least one of R 1  and R 2  is alkyl that is unsubstituted or substituted with halo-. In another example, both R 1  and R 2  are independently alkyl that is unsubstituted or substituted with halo-. In some embodiments, at least one of R 1  and R 2  is methyl. In other embodiments, R 1  and R 2  are methyl. 
     In some embodiments, x+y+z is at least 3. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A] x , when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. Similarly, when u is greater than 1, each compound can encompass peptidomimetic macrocycles which are the same or different. For example, a compound can comprise peptidomimetic macrocycles comprising different linker lengths or chemical compositions. 
     In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is an α-helix and R 8  is —H, allowing for intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an α,α-disubstituted amino acid. In one example, B is an α,α-disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. In other embodiments, at least one of A, B, C, D or E is 
     
       
         
         
             
             
         
       
     
     In other embodiments, the length of the macrocycle-forming linker L as measured from a first Cα to a second Cα is selected to stabilize a desired secondary peptide structure, such as an α-helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Cα to a second Cα. 
     In some embodiments, a peptidomimetic macrocycle of Formula (I) has Formula (Ia): 
     
       
         
         
             
             
         
       
     
     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 -];
         each L is independently a macrocycle-forming linker;   each L′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R 5 , or a bond, or together with R 1  and the atom to which both R 1  and L′ are bound forms a ring;   each L″ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R 5 , or a bond, or together with R 2  and the atom to which both R 2  and L″ are bound forms a ring;   each R 1  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-, or together with L′ and the atom to which both R 1  and L′ are bound forms a ring;   each R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-, or together with L″ and the atom to which both R 2  and L″ are bound forms a ring;   R 3  is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R 5 ;   each L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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, CO 2 , or CONR 3 ;   n is an integer from 1-5;   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;   each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;   each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;   each v and w is independently an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-40, 1-25, 1-20, 1-15, or 1-10; and   each u, x, y and z is independently an integer from 0-10.       

     In some embodiments, L is a macrocycle-forming linker of the formula -L 1 -L 2 -. In some embodiments, L 1  and L 2  are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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, CO 2 , or CONR 3 ; and n is an integer from 1-5. 
     In one example, at least one of R 1  and R 2  is alkyl that is unsubstituted or substituted with halo-. In another example, both R 1  and R 2  are independently alkyl that is unsubstituted or substituted with halo-. In some embodiments, at least one of R 1  and R 2  is methyl. In other embodiments, R 1  and R 2  are methyl. 
     In some embodiments, x+y+z is at least 2. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A] x , when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. Similarly, when u is greater than 1, each compound may encompass peptidomimetic macrocycles which are the same or different. For example, a compound may comprise peptidomimetic macrocycles comprising different linker lengths or chemical compositions. 
     In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is a helix and R 8  is —H, allowing intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an α,α-disubstituted amino acid. In one example, B is an α,α-disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. 
     In other embodiments, at least one of A, B, C, D or E is 
     
       
         
         
             
             
         
       
     
     In other embodiments, the length of the macrocycle-forming linker L as measured from a first Cα to a second Cα is selected to stabilize a desired secondary peptide structure, such as a helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Cα to a second Cα. 
     In one embodiment, the peptidomimetic macrocycle of Formula (I) is: 
     
       
         
         
             
             
         
       
     
     wherein each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 
     In related embodiments, the peptidomimetic macrocycle of Formula (I) is: 
     
       
         
         
             
             
         
       
     
     wherein each R 1 ′ and R 2 ′ is independently an amino acid. 
     In other embodiments, the peptidomimetic macrocycle of Formula (I) is a compound of any of the formulas shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein “AA” represents any natural or non-natural amino acid side chain and “ ” is [D] v , [E] w  as defined above, and n is an integer between 0 and 20, 50, 100, 200, 300, 400 or 500. In some embodiments, n is 0. In other embodiments, n is less than 50. 
     Exemplary embodiments of the macrocycle-forming linker L are shown below. 
     
       
         
         
             
             
         
       
     
     In other embodiments, D and/or E in the compound of Formula (I) are further modified in order to facilitate cellular uptake. In some embodiments, lipidating or PEGylating a peptidomimetic macrocycle facilitates cellular uptake, increases bioavailability, increases blood circulation, alters pharmacokinetics, decreases immunogenicity, and/or decreases the needed frequency of administration. 
     In other embodiments, at least one of [D] and [E] in the compound of Formula (I) represents a moiety comprising an additional macrocycle-forming linker such that the peptidomimetic macrocycle comprises at least two macrocycle-forming linkers. In a specific embodiment, a peptidomimetic macrocycle comprises two macrocycle-forming linkers. In one embodiment, u is 2. 
     In some embodiments, the peptidomimetic macrocycles have the 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 -];
         each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;   each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R 5 ;   each L is independently macrocycle-forming linker of the formula:       

     
       
         
         
             
             
         
       
         
         
           
             wherein each L 1 , L 2  and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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 independently O, S, SO, SO 2 , CO, 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; 
             each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; 
             each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
             each v and w is independently an integer from 1-1000; 
             each u, x, y and z is independently integers from 0-10; and 
             n is an integer from 1-5. 
           
         
       
    
     In one example, at least one of R 1  and R 2  is alkyl that is unsubstituted or substituted with halo-. In another example, both R 1  and R 2  are independently alkyl that is unsubstituted or substituted with halo-. In some embodiments, at least one of R 1  and R 2  is methyl. In other embodiments, R 1  and R 2  are methyl. 
     In some embodiments, x+y+z is at least 2. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A] x , when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. 
     In some embodiments, each of the first two amino acid represented by E comprises an uncharged side chain or a negatively charged side chain. In some embodiments, each of the first three amino acid represented by E comprises an uncharged side chain or a negatively charged side chain. In some embodiments, each of the first four amino acid represented by E comprises an uncharged side chain or a negatively charged side chain. In some embodiments, one or more or each of the amino acid that is i+1, i+2, i+3, i+4, i+5, and/or i+6 with respect to E comprises an uncharged side chain or a negatively charged side chain. 
     In some embodiments, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprises a hydrophobic side chain, for example a small hydrophobic side chain. In some embodiments, the first C-terminal amino acid, the second C-terminal amino acid, and/or the third C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, the first C-terminal amino acid, the second C-terminal amino acid, and/or the third C-terminal amino acid represented by E comprises a hydrophobic side chain, for example a small hydrophobic side chain. In some embodiments, one or more or each of the amino acid that is i+1, i+2, i+3, i+4, i+5, and/or i+6 with respect to E comprises an uncharged side chain or a negatively charged side chain. 
     In some embodiments, w is between 1 and 1000. For example, the first amino acid represented by E comprises a small hydrophobic side chain. In some embodiments, w is between 2 and 1000. For example, the second amino acid represented by E comprises a small hydrophobic side chain. In some embodiments, w is between 3 and 1000. For example, the third amino acid represented by E comprises a small hydrophobic side chain. For example, the third amino acid represented by E comprises a small hydrophobic side chain. In some embodiments, w is between 4 and 1000. In some embodiments, w is between 5 and 1000. In some embodiments, w is between 6 and 1000. In some embodiments, w is between 7 and 1000. In some embodiments, w is between 8 and 1000. 
     In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is a helix and R 8  is —H, allowing intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an α,α-disubstituted amino acid. In one example, B is an α,α-disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. 
     In other embodiments, at least one of A, B, C, D or E is 
     
       
         
         
             
             
         
       
     
     In other embodiments, the length of the macrocycle-forming linker L as measured from a first Cα to a second Cα is selected to stabilize a desired secondary peptide structure, such as a helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Cα to a second Cα. 
     In some embodiments, L is a macrocycle-forming linker of the formula 
     
       
         
         
             
             
         
       
     
     In some embodiments, L is a macrocycle-forming linker of the formula 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof. 
     Exemplary embodiments of the macrocycle-forming linker L are shown below. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Amino acids which are used in the formation of triazole crosslinkers are represented according to the legend indicated below. Stereochemistry at the alpha position of each amino acid is S unless otherwise indicated. For azide amino acids, the number of carbon atoms indicated refers to the number of methylene units between the alpha carbon and the terminal azide. For alkyne amino acids, the number of carbon atoms indicated is the number of methylene units between the alpha position and the triazole moiety plus the two carbon atoms within the triazole group derived from the alkyne.
         $5a5 Alpha-Me alkyne 1,5 triazole (5 carbon)   $5n3 Alpha-Me azide 1,5 triazole (3 carbon)   $4rn6 Alpha-Me R-azide 1,4 triazole (6 carbon)   $4a5 Alpha-Me alkyne 1,4 triazole (5 carbon)       

     In some embodiments, the peptidomimetic macrocycle comprises at least one α-helix motif. For example, A, B and/or C in the compound of Formula (I) include one or more α-helices. As a general matter, α-helices include between 3 and 4 amino acid residues per turn. In some embodiments, the α-helix of the peptidomimetic macrocycle includes 1 to 5 turns and, therefore, 3 to 20 amino acid residues. In specific embodiments, the α-helix includes 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns. In some embodiments, the macrocycle-forming linker stabilizes an α-helix motif included within the peptidomimetic macrocycle. Thus, in some embodiments, the length of the macrocycle-forming linker L from a first Cα to a second Cα is selected to increase the stability of an α-helix. In some embodiments, the macrocycle-forming linker spans from 1 turn to 5 turns of the α-helix. In some embodiments, the macrocycle-forming linker spans approximately 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns of the α-helix. In some embodiments, the length of the macrocycle-forming linker is approximately 5 Å to 9 Å per turn of the α-helix, or approximately 6 Å to 8 Å per turn of the α-helix. Where the macrocycle-forming linker spans approximately 1 turn of an α-helix, the length is equal to approximately 5 carbon-carbon bonds to 13 carbon-carbon bonds, approximately 7 carbon-carbon bonds to 11 carbon-carbon bonds, or approximately 9 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 2 turns of an α-helix, the length is equal to approximately 8 carbon-carbon bonds to 16 carbon-carbon bonds, approximately 10 carbon-carbon bonds to 14 carbon-carbon bonds, or approximately 12 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 3 turns of an α-helix, the length is equal to approximately 14 carbon-carbon bonds to 22 carbon-carbon bonds, approximately 16 carbon-carbon bonds to 20 carbon-carbon bonds, or approximately 18 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 4 turns of an α-helix, the length is equal to approximately 20 carbon-carbon bonds to 28 carbon-carbon bonds, approximately 22 carbon-carbon bonds to 26 carbon-carbon bonds, or approximately 24 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 5 turns of an α-helix, the length is equal to approximately 26 carbon-carbon bonds to 34 carbon-carbon bonds, approximately 28 carbon-carbon bonds to 32 carbon-carbon bonds, or approximately 30 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 1 turn of an α-helix, the linkage contains approximately 4 atoms to 12 atoms, approximately 6 atoms to 10 atoms, or approximately 8 atoms. Where the macrocycle-forming linker spans approximately 2 turns of the α-helix, the linkage contains approximately 7 atoms to 15 atoms, approximately 9 atoms to 13 atoms, or approximately 11 atoms. Where the macrocycle-forming linker spans approximately 3 turns of the α-helix, the linkage contains approximately 13 atoms to 21 atoms, approximately 15 atoms to 19 atoms, or approximately 17 atoms. Where the macrocycle-forming linker spans approximately 4 turns of the α-helix, the linkage contains approximately 19 atoms to 27 atoms, approximately 21 atoms to 25 atoms, or approximately 23 atoms. Where the macrocycle-forming linker spans approximately 5 turns of the α-helix, the linkage contains approximately 25 atoms to 33 atoms, approximately 27 atoms to 31 atoms, or approximately 29 atoms. Where the macrocycle-forming linker spans approximately 1 turn of the α-helix, the resulting macrocycle forms a ring containing approximately 17 members to 25 members, approximately 19 members to 23 members, or approximately 21 members. Where the macrocycle-forming linker spans approximately 2 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 29 members to 37 members, approximately 31 members to 35 members, or approximately 33 members. Where the macrocycle-forming linker spans approximately 3 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 44 members to 52 members, approximately 46 members to 50 members, or approximately 48 members. Where the macrocycle-forming linker spans approximately 4 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 59 members to 67 members, approximately 61 members to 65 members, or approximately 63 members. Where the macrocycle-forming linker spans approximately 5 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 74 members to 82 members, approximately 76 members to 80 members, or approximately 78 members. 
     In other embodiments, provided are peptidomimetic macrocycles of Formula (II) or (IVa): 
     
       
         
         
             
             
         
       
     
     wherein:
         each A, C, D, and E is independently a natural or non-natural amino acid, and the terminal D and E independently optionally include a capping group;   B is 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, unsubstituted or substituted with halo-; or at least one of R 1  and R 2  forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;   R 3  is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R 5 ;   L is a macrocycle-forming linker of the formula -L 1 -L 2 -;   L 1  and L 2  and L 3  are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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, 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, aryl, or heteroaryl, optionally substituted with R 5 ;   v and w are independently integers from 1-1000;   u is an integer from 1-10;   x, y and z are independently integers from 0-10; and   n is an integer from 1-5.       

     In one example, L 1  and L 2 , either alone or in combination, do not form a triazole or a thioether. 
     In one example, at least one of R 1  and R 2  is alkyl that is unsubstituted or substituted with halo-. In another example, both R 1  and R 2  are independently alkyl that is unsubstituted or substituted with halo-. In some embodiments, at least one of R 1  and R 2  is methyl. In other embodiments, R 1  and R 2  are methyl. 
     In some embodiments, x+y+z is at least 1. In other embodiments, x+y+z is at least 2. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A] x , when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. 
     In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is an α-helix and R 8  is —H, allowing intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an α,α-disubstituted amino acid. In one example, B is an α,α-disubstituted amino acid. For example, at least one of A, B, C, D or E is 2-aminoisobutyric acid. 
     In other embodiments, at least one of A, B, C, D or E is 
     
       
         
         
             
             
         
       
     
     In other embodiments, the length of the macrocycle-forming linker L as measured from a first Cα to a second Cα is selected to stabilize a desired secondary peptide structure, such as an cc-helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Cα to a second Cα. 
     Exemplary embodiments of the macrocycle-forming linker -L 1 -L 2 - are shown below. 
     
       
         
         
             
             
         
       
     
     In some embodiments, the peptidomimetic macrocycle has the Formula (III) or Formula (IIIa): 
     
       
         
         
             
             
         
       
     
     wherein:
         each A a , C a , D a , E a , A b , C b , and D b  is independently a natural or non-natural amino acid;   each B a  and B b  is independently a natural or non-natural amino acid,       

     
       
         
         
             
             
         
       
     
     [—NH-L 4 -CO—], [—NH-L 4 -SO 2 —], or [—NH-L 4 -];
         each R a1  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R a1  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D a  or E a  amino acids; or together with L a  forms a ring that is unsubstituted or substituted;   each R a2  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R a2  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D a  or E a  amino acids; or together with L a  forms a ring that is unsubstituted or substituted;   each R b1  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R b1  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D b  amino acids; or together with L b  forms a ring that is unsubstituted or substituted;   each R 3  is independently, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted, or H;   each L a  is independently a macrocycle-forming linker, and optionally forms a ring with R a1  or R a2  that is unsubstituted or substituted;   each L b  is independently a macrocycle-forming linker, and optionally forms a ring with R b1  that is unsubstituted or substituted;   each L′ is independently a macrocycle-forming linker;   each L 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , any of which is unsubstituted or substituted;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , OSO 2 NR 3 , NR 3q , CONR 3q , OCONR 3q , or OSO 2 NR 3q , wherein each R 3q  is independently a point of attachment to R a1 , R a2 , or R b1 ;   R a7  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with a D a  amino acid;   R b7  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with a D b  amino acid;   R a8  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with an E a  amino acid;   R b8  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or an amino acid sequence of 1-1000 amino acid residues;   each va and vb is independently an integer from 0-1000;   each wa and wb is independently an integer from 0-1000;   each ua and ub is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein ua+ub is at least 1;   each xa and xb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   each ya and yb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   each za and zb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and   each n is independently 1, 2, 3, 4, or 5,
 
or a pharmaceutically-acceptable salt thereof.
       

     In some embodiments, the peptidomimetic macrocycle has the Formula (III) or Formula (IIIa): 
     
       
         
         
             
             
         
       
     
     wherein:
         each A a , C a , D a , E a , A b , C b , and D b  is independently a natural or non-natural amino acid;   each B a  and B b  is independently a natural or non-natural amino acid,       

     
       
         
         
             
             
         
       
     
     [—NH-L 4 -CO—], [—NH-L 4 -SO 2 —], or [—NH-L 4 -];
         each R a1  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R a1  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D a  or E a  amino acids; or together with L a  forms a ring that is unsubstituted or substituted;   each R a2  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R a2  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D a  or E a  amino acids; or together with L a  forms a ring that is unsubstituted or substituted;   each R b1  is independently, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, any of which is unsubstituted or substituted; or H; or R b1  forms a macrocycle-forming linker L′ connected to the alpha position of one of the D b  amino acids; or together with L b  forms a ring that is unsubstituted or substituted;   each R 3  is independently, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 , or H;   each L a  is independently a macrocycle-forming linker, and optionally forms a ring with R a1  or R a2  that is unsubstituted or substituted;   each L b  is independently a macrocycle-forming linker, and optionally forms a ring with R b1  that is unsubstituted or substituted;   each L′ is independently a macrocycle-forming linker;   each L 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , any of which is unsubstituted or substituted with R 5 ;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , OSO 2 NR 3 , NR 3q , CONR 3q , OCONR 3q , or OSO 2 NR 3q , wherein each R 3q  is independently a point of attachment to R a1 , R a2 , or R b1 ;   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 a7  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or part of a cyclic structure with a D a  amino acid;   R b7  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or part of a cyclic structure with a D b  amino acid;   R a8  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or part of a cyclic structure with an E a  amino acid;   R b8  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or an amino acid sequence of 1-1000 amino acid residues;   each va and vb is independently an integer from 0-1000;   each wa and wb is independently an integer from 0-1000;   each ua and ub is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein ua+ub is at least 1;   each xa and xb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   each ya and yb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;   each za and zb is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and   each n is independently 1, 2, 3, 4, or 5,
 
or a pharmaceutically-acceptable salt thereof.
       

     In some embodiments, the peptidomimetic macrocycle of the invention has the formula defined above, wherein:
         each L a  is independently a macrocycle-forming linker of the formula -L 1 -L 2 -, and optionally forms a ring with R a1  or R a2  that is unsubstituted or substituted;   each L b  is independently a macrocycle-forming linker of the formula -L 1 -L 2 -, and optionally forms a ring with R b1  that is unsubstituted or substituted;   each L′ is independently a macrocycle-forming linker of the formula -L 1 -L 2 -;   each L 1  and L 2  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , any of which is unsubstituted or substituted with R 5 ;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , OSO 2 NR 3 , NR 3q , CONR 3q , OCONR 3q , or OSO 2 NR 3q , wherein each R 3q  is independently a point of attachment to R a1 , R a2 , or R b1 ;   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; and   each R 6  is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent, or a pharmaceutically-acceptable salt thereof.       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L a  and L b  is independently a triazole-containing macrocycle-forming linker. In some embodiments, the peptidomimetic macrocycle has the formula defined above, wherein:
         each L a  and L b  is independently 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 , any of which is unsubstituted or substituted with R 5 ; 
             each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ; 
             each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , or OSO 2 NR 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; and 
             each n is independently 1, 2, 3, 4, or 5,
 
or a pharmaceutically-acceptable salt thereof.
 
           
         
       
    
     In some embodiments, the peptidomimetic macrocycle has the formula defined above, wherein:
         each L a  and L b  is independently a macrocycle-forming linker of the formula -L 1 -SR 9 R 10 -L 2 -SR 11 R 12 -L 3 -, wherein 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 , any of which is unsubstituted or substituted with R 5 ; and each R 9 , R 10 , R 11 , and R 12  is independently absent or O;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , OSO 2 NR 3 , NR 3q , CONR 3q , OCONR 3q , or OSO 2 NR 3q , wherein each R 3q  is independently a point of attachment to R a1 , R a2 , or R b1 ;   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; and   each n is independently 1, 2, 3, 4, or 5,
 
or a pharmaceutically-acceptable salt thereof.
       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein one or both L a  and L b  is independently a bis-thioether-containing macrocycle-forming linker. In some embodiments, each L a  and L b  is independently a macrocycle-forming linker of the formula -L 1 -S-L 2 -S-L 3 -. 
     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein one or both L a  and L b  is independently a bis-sulfone-containing macrocycle-forming linker. In some embodiments, each L a  and L b  is independently a macrocycle-forming linker of the formula -L 1 -SO 2 -L 2 -SO 2 -L 3 -. 
     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein one or both L a  and L b  is independently a bis-sulfoxide-containing macrocycle-forming linker. In some embodiments, each L a  and L b  is independently a macrocycle-forming linker of the formula -L 1 -S(O)-L 2 -S(O)-L 3 -. 
     In some embodiments, a peptidomimetic macrocycle of the invention comprises one or more secondary structures. In some embodiments, the peptidomimetic macrocycle comprises a secondary structure that is an α-helix. In some embodiments, the peptidomimetic macrocycle comprises a secondary structure that is a β-hairpin turn. 
     In some embodiments, u a  is 0. In some embodiments, u a  is 0, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u a  is 0, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u a  is 0, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u a  is 0, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u a  is 0, and L b  is a sulfur-containing macrocycle-forming linker. 
     In some embodiments, u b  is 0. In some embodiments, u b  is 0, and L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u b  is 0, and L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u b  is 0, and L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u b  is 0, and L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u b  is 0, and L a  is a sulfur-containing macrocycle-forming linker. 
     In some embodiments, the peptidomimetic macrocycle comprises only α-helical secondary structures. In other embodiments, the peptidomimetic macrocycle comprises only β-hairpin secondary structures. 
     In other embodiments, the peptidomimetic macrocycle comprises a combination of secondary structures, wherein the secondary structures are α-helical and β-hairpin structures. In some embodiments, L a  and L b  are a combination of hydrocarbon-, triazole, or sulfur-containing macrocycle-forming linkers. In some embodiments, the peptidomimetic macrocycle comprises L a  and L b , wherein L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical structure. In some embodiments, the peptidomimetic macrocycle comprises L a  and L b , wherein L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin structure. In some embodiments, the peptidomimetic macrocycle comprises L a  and L b , wherein L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure. In some embodiments, the peptidomimetic macrocycle comprises L a  and L b , wherein L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure. 
     In some embodiments, u a +u b  is at least 1. In some embodiments, u a +u b =2. 
     In some embodiments, u a  is 1, and u b  is 1. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks an α-helical secondary structure, and L b  is a sulfur-containing macrocycle-forming linker. In some embodiments, u a  is 1, u b  is 1, L a  is a triazole-containing macrocycle-forming linker that crosslinks a β-hairpin secondary structure, and L b  is a sulfur-containing macrocycle-forming linker. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a sulfur-containing macrocycle-forming linker, and L b  is a triazole-containing macrocycle-forming linker with an α-helical secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a sulfur-containing macrocycle-forming linker, and L b  is a triazole-containing macrocycle-forming linker with a β-hairpin secondary structure. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker with an α-helical secondary structure, and L b  is a sulfur-containing macrocycle-forming linker. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker with a β-hairpin secondary structure, and L b  is a sulfur-containing macrocycle-forming linker. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a sulfur-containing macrocycle-forming linker, and L b  is a hydrocarbon-containing macrocycle-forming linker with an α-helical secondary structure. In some embodiments, u a  is 1, u b  is 1, L a  is a sulfur-containing macrocycle-forming linker, and L b  is a hydrocarbon-containing macrocycle-forming linker with a β-hairpin secondary structure. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a sulfur-containing macrocycle-forming linker, and L b  is a sulfur-containing macrocycle-forming linker. 
     In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks an α-helical structure. In some embodiments, u a  is 1, u b  is 1, L a  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure, and L b  is a hydrocarbon-containing macrocycle-forming linker that crosslinks a β-hairpin structure. 
     In some embodiments, R b1  is H. 
     In some embodiments, the peptidomimetic macrocycle has the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
         each L is independently a macrocycle-forming linker;   each AA 1  to AA 20  is independently a natural or non-natural amino acid;   each z 1  to z 20  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the sum of z 1  to z 20  is at least 6; and   R q  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted; or H; or part of a cyclic structure with a neighboring amino acid;
 
or a pharmaceutically-acceptable salt thereof.
       

     In some embodiments, the peptidomimetic macrocycle has the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
         each L is independently a macrocycle-forming linker;   each AA 1  to AA 20  is independently a natural or non-natural amino acid;   each z 1  to z 20  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the sum of z 1  to z 20  is at least 6;   R q  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or part of a cyclic structure with a neighboring amino acid;   R 5  is 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; and   each R 6  is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent,
 
or a pharmaceutically-acceptable salt thereof.
       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above, wherein L is a hydrocarbon-containing macrocycle-forming linker. In some embodiments, each L is independently a macrocycle-forming linker of the formula -L 1 -L 2 - that optionally forms a ring with a neighboring amino acid that is unsubstituted or substituted, wherein:
         each L 1  and L 2  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , any of which is unsubstituted or substituted with R 5 ;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ; and   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , or OSO 2 NR 3 ;   R 5  is 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; and   each n is independently 1, 2, 3, 4, or 5.       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L is independently a triazole-containing macrocycle-forming linker. In some embodiments each L is independently a macrocycle-forming linker of the formula 
     
       
         
         
             
             
         
       
     
     wherein:
         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 , any of which is unsubstituted or substituted with R 5 ;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , OSO 2 NR 3 , NR 3q , CONR 3q , OCONR 3q , or OSO 2 NR 3q , wherein each R 3q  is independently a point of attachment to R a1 , R a2 , or R b1 ,   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; and   each n is independently 1, 2, 3, 4, or 5.       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L is independently a sulfur-containing macrocycle-forming linker. In some embodiments, each L is independently a macrocycle-forming linker of the formula -L 1 -SR 9 R 10 -L 2 -SR 11 R 12 -L 3 -, wherein:
         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 , any of which is unsubstituted or substituted with R 5 ; and each R 9 , R 10 , R 11 , and R 12  is independently absent or O;   each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, any of which is unsubstituted or substituted with R 5 ;   each K is independently O, S, SO, SO 2 , CO, CO 2 , OCO 2 , NR 3 , CONR 3 , OCONR 3 , or OSO 2 NR 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; and   each n is independently 1, 2, 3, 4, or 5.       

     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L is independently a bis-thioether-containing macrocycle-forming linker. In some embodiments, each L is independently a macrocycle-forming linker of the formula -L 1 -S-L 2 -S-L 3 -. 
     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L is independently a bis-sulfone-containing macrocycle-forming linker. In some embodiments, each L is independently a macrocycle-forming linker of the formula -L 1 -SO 2 -L 2 -SO 2 -L 3 -. 
     In some embodiments, the peptidomimetic macrocycle has the formula defined above wherein each L is independently a bis-sulfoxide-containing macrocycle-forming linker. In some embodiments, each L is independently a macrocycle-forming linker of the formula -L 1 -S(O)-L 2 -S(O)-L 3 -. 
     In some embodiments, L is connected to an acylated N-terminus of an amino acid chain on one end is connected to the amidated C-terminus of the amino acid chain on a second end. In some embodiments, the amidated C-terminus of an amino acid chain is of the formula NR q , wherein R q  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, any of which is unsubstituted or substituted with R 5 ; or H; or part of a cyclic structure with a neighboring amino acid. 
     In some embodiments, each z 1  to z 20  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and the sum of z 1  to z 20  is at least 6. In some embodiments, each z 1  to z 20  is independently 0-2. In some embodiments, each z 1  to z 20  is 0 or 1. In some embodiments, the sum of z 1  to z 20  is 6-30. In some embodiments, the sum of z 1  to z 20  is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. 
     In some embodiments, the sum of z 1  to z 20  is 12. In some embodiments, the sum of z 1  to z 20  is 12-15. In some embodiments, the sum of z 1  to z 20  is 15-30. In some embodiments, the sum of z 1  to z 20  is 30-45. In some embodiments, the sum of z 1  to z 20  is 50-75. In some embodiments, the sum of z 1  to z 20  is 75-150. In some embodiments, the sum of z 1  to z 20  is 150-200. 
     In some embodiments, the peptidomimetic macrocycles of the invention are charged. In some embodiments, the peptidomimetic macrocycles of the invention are positively charged. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +1 to +20. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +1, +2, +3, +4, +5, +6, +7, +8, +9, +10, +11, +12, +13, +14, +15, +16, +17, +18, +19, or +20. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +1 to +3. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +5. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +7. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +10 to +12. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of +15 to +20. 
     In some embodiments, the peptidomimetic macrocycles of the formula described above have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 positive charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 3 to 5 positive charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 7 to 10 positive charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 15 to 20 positive charges. 
     In some embodiments, the peptidomimetic macrocycles of the invention are negatively charged. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −1 to −20. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −1, −2, −3, −4, −5, −6, −7, −8, −9, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, or −20. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −1 to −3. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −5. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −7. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −10 to −12. In some embodiments, the peptidomimetic macrocycles of the formula described above have a net charge of −15 to −20. 
     In some embodiments, the peptidomimetic macrocycles of the formula described above have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 negative charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 3 to 5 negative charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 7 to 10 negative charges. In some embodiments, the peptidomimetic macrocycles of the formula described above have 15 to 20 negative charges. 
     In some embodiments, the peptidomimetic macrocycle described above has at least 1 pair of neighboring identical amino acids. In some embodiments, the peptidomimetic macrocycle has 1 pair of neighboring identical amino acids. In other embodiments, the peptidomimetic macrocycle has 3 pairs of neighboring identical amino acids. In other embodiments, the peptidomimetic macrocycle has 5 pairs of neighboring identical amino acids. 
     Unless otherwise stated, any compounds (including peptidomimetic macrocycles, macrocycle precursors, and other compositions) are also meant to encompass compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the described structures except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by  13 C- or  14 C are contemplated. 
     In some embodiments, a peptidomimetic macrocycle having the Formula (A) can be used as an antibiotic to target LptD. The peptidomimetic macrocycle can be active in the nanomolar range against Gram-negative  Pseudomonas  spp. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a peptidomimetic macrocycle having the Formula (B) can be used as an antibiotic to target LptD. The peptidomimetic macrocycle can exhibit potent antimicrobial activity against  Escherichia coli.  The peptidomimetic macrocycle can interact with OM proteins, such as BamA or LptD. 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compounds disclosed herein (e.g., peptidomimetic macrocycle) can contain a macrocycle-forming linker that can stabilize β-hairpin conformations within the macrocycle. In some embodiments, the macrocycle-forming linker is a D-proline-L-proline sequence. In some embodiments, the macrocycle-forming linker is a hydrocarbon linker. In some embodiments, the macrocycle-forming linker is a 1,4 triazole linker. 
     Non-limiting examples of the peptidomimetic macrocycles are shown below. Residues with the notation “$” represent residues that can be substituted with a residue capable of forming a crosslink with a second residue in the same molecule or a precursor of such residue. 
     
       
         
           
               
            
               
                 SEQ ID NO. 1 
               
               
                 Ac- D N E Q D M I V K E M Y D R A A E Q L I R K L 
               
               
                   
               
               
                 NH2 
               
               
                   
               
               
                 SEQ ID NO. 2 
               
               
                 Ac- D N E Q D M I V K E $ Y D R $ A E Q L I R K L 
               
               
                   
               
               
                 NH2 
               
               
                   
               
               
                 SEQ ID NO. 3 
               
               
                 Ac- D N E Q D M I V K E Nle $ D R A $ E Q L I R K 
               
               
                   
               
               
                 L NH2 
               
               
                   
               
               
                 SEQ ID NO. 4 
               
               
                 Ac- D N E $ D M I $ K E Nle Y D R A A E Q L I R K 
               
               
                   
               
               
                 L NH2 
               
               
                   
               
               
                 SEQ ID NO. 5 
               
               
                 Ac- D N E Q D M V K E $ Y D R A A E Q L I R K L 
               
               
                   
               
               
                 NH2 
               
               
                   
               
               
                 SEQ ID NO. 6 
               
               
                 Ac- D N E Q D M I V K E Nle Y D R A $ E Q L R K 
               
               
                   
               
               
                 L NH2 
               
            
           
         
       
     
     Two or more peptides can share a degree of homology. In some embodiments, peptidomimetic macrocycles of the invention comprise amino acid sequences with about 20% to up to about 99.9% pairwise homology to SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6. In some embodiments, the peptidomimetic macrocycles of the invention can have up to about 20% pairwise homology, up to about 25% pairwise homology, up to about 30% pairwise homology, up to about 35% pairwise homology, up to about 40% pairwise homology, up to about 45% pairwise homology, up to about 50% pairwise homology, up to about 55% pairwise homology, up to about 60% pairwise homology, up to about 65% pairwise homology, up to about 70% pairwise homology, up to about 75% pairwise homology, up to about 80% pairwise homology, up to about 85% pairwise homology, up to about 90% pairwise homology, up to about 95% pairwise homology, up to about 96% pairwise homology, up to about 97% pairwise homology, up to about 98% pairwise homology, up to about 99% pairwise homology, up to about 99.5% pairwise homology, or up to about 99.9% pairwise homology to SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6. In some embodiments, the peptidomimetic macrocycles of the invention can have, for example, at least about 20% pairwise homology, at least about 25% pairwise homology, at least about 30% pairwise homology, at least about 35% pairwise homology, at least about 40% pairwise homology, at least about 45% pairwise homology, at least about 50% pairwise homology, at least about 55% pairwise homology, at least about 60% pairwise homology, at least about 65% pairwise homology, at least about 70% pairwise homology, at least about 75% pairwise homology, at least about 80% pairwise homology, at least about 85% pairwise homology, at least about 90% pairwise homology, at least about 95% pairwise homology, at least about 96% pairwise homology, at least about 97% pairwise homology, at least about 98% pairwise homology, at least about 99% pairwise homology, at least about 99.5% pairwise homology, at least about 99.9% pairwise homology to SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, OR SEQ ID NO. 6. 
     Various methods and software programs can be used to determine the homology between two or more peptides, such as NCBI BLAST, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, or another suitable method or algorithm. 
     In some embodiments, the secondary structures of the peptidomimetic macrocycles of the invention are more stable than the corresponding secondary structure of a corresponding non-macrocyclic polypeptide. In some embodiments, the peptidomimetic macrocycles of the invention comprise at least one helical structure. In some embodiments, the peptidomimetic macrocycles of the invention comprise at least one α-helical structure. In some embodiments, the peptidomimetic macrocycles of the invention comprise at least one 3 10 -helical structure. In some embodiments, the peptidomimetic macrocycles of the invention comprise an α-helix, and the α-helix is more stable than an α-helix of a corresponding non-macrocyclic polypeptide. In some embodiments, the peptidomimetic macrocycles comprise 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. 
     In some embodiments, the peptidomimetic macrocycles comprise α-helices in an aqueous solution. In some embodiments, the peptidomimetic macrocycles comprise increased α-helical structures in an aqueous solution compared to corresponding non-macrocyclic polypeptides. 
     In some embodiments, the peptidomimetic macrocycles exhibit increased biological activity compared to the corresponding non-peptidomimetic polypeptides. In some embodiments, the peptidomimetic macrocycles exhibit increased thermal stability compared to corresponding non-macrocyclic polypeptides. In some embodiments, the peptidomimetic macrocycles exhibit increased resistance to proteolytic degradation compared to corresponding non-macrocyclic polypeptides. In some embodiments, the peptidomoimetic macrocycles exhibit an increased ability to penetrate living cells compared to a corresponding non-macrocyclic polypeptide. 
     In some embodiments, the peptidomimetic macrocycles have β-helical secondary structures, and the peptidomimetic macrocycles are more stable than the corresponding β-helical secondary structures of the corresponding non-macrocyclic polypeptides. In some embodiments, the peptidomimetic macrocycles comprise β-hairpin turns in an aqueous solution. In some embodiments, the peptidomimetic macrocycles exhibit increased β-hairpin structures in aqueous solutions compared to corresponding non-macrocyclic polypeptides. 
     EXAMPLES 
     Example 1 
     Preparation of Peptidomimetic Macrocycles 
     The preparation of peptidomimetic macrocycles is described in Schafmeister et al., J. Am. Chem. Soc. 122:5891-5892 (2000); Schafmeister &amp; Verdin, J. Am. Chem. Soc. 122:5891 (2005); Walensky et al., Science 305:1466-1470 (2004); U.S. Pat. No. 7,192,713 and PCT application WO 2008/121767. The α,α-disubstituted amino acids and amino acid precursors disclosed in the cited references can be employed in synthesis of the peptidomimetic macrocycle precursor polypeptides. For example, the “S5-olefin amino acid” is (S)-α-(2′-pentenyl) alanine and the “R8 olefin amino acid” is (R)-α-(2′-octenyl) alanine. Following incorporation of such amino acids into precursor polypeptides, the terminal olefins are reacted with a metathesis catalyst, leading to the formation of the peptidomimetic macrocycle. In various embodiments, the following amino acids can be employed in the synthesis of the peptidomimetic macrocycle: 
     
       
         
         
             
             
         
       
     
     In other embodiments, the peptidomimetic macrocycles are of Formula (II) or (IIa). Methods for the preparation of such macrocycles are described, for example, in U.S. Pat. No. 7,202,332. 
     Additional methods of forming peptidomimetic macrocycles which are envisioned as suitable include those disclosed by Mustapa et al., J. Org. Chem. (2003), 68, pp. 8193-8198; Yang et al. Bioorg. Med. Chem. Lett. (2004), 14, pp. 1403-1406; U.S. Pat. No. 5,364,851; U.S. Pat. No. 5,446,128; U.S. Pat. No. 5,824,483; U.S. Pat. No. 6,713,280; and U.S. Pat. No. 7,202,332. 
     Example 2 
     Assay to Determine Melting Temperature (T m ) 
     A peptidomimetic macrocycle comprising a secondary structure such as an α-helix exhibits, for example, a higher melting temperature than a corresponding uncrosslinked polypeptide. Typically peptidomimetic macrocycles exhibit Tm of &gt;60° C. representing a highly stable structure in aqueous solutions. To assay the effect of macrocycle formation on melting temperature, peptidomimetic macrocycles or unmodified peptides are dissolved in distilled H 2 O (e.g. at a final concentration of 50 μM) and the T m  is determined by measuring the change in ellipticity over a temperature range (e.g. 4 to 95° C.) on a spectropolarimeter (e.g., Jasco J-710) using standard parameters (e.g. wavelength 222 nm; step resolution, 0.5 nm; speed, 20 nm/sec; accumulations, 10; response, 1 sec; bandwidth, 1 nm; temperature increase rate: 1° C./min; path length, 0.1 cm). 
     Example 3 
     Protease Resistance Assay 
     The amide bond of the peptide backbone is susceptible to hydrolysis by proteases, thereby rendering peptidic compounds vulnerable to rapid degradation in vivo. Peptide helix formation, however, typically buries the amide backbone and therefore can shield it from proteolytic cleavage. The peptidomimetic macrocycles can be subjected to in vitro trypsin proteolysis to assess for any changes in degradation rates compared to a corresponding uncrosslinked polypeptide. For example, the peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide are incubated with trypsin agarose, and the reactions are quenched at various time points by centrifugation; subsequent HPLC injections are used to quantify the residual substrate based on ultraviolet absorption at 280 nm. Briefly, the peptidomimetic macrocycle and peptidomimetic precursor (5 mcg) are incubated with trypsin agarose (Pierce) (S/E ˜125) for 0, 10, 20, 90, and 180 minutes. Reactions are quenched by tabletop centrifugation at high speed; the remaining substrate in the isolated supernatant is quantified by HPLC-based peak detection at 280 nm. The proteolytic reaction displays first order kinetics and the rate constant, k, is determined from a plot of 1n[S] versus time (k=−1×slope). 
     Example 4 
     Ex Vivo Stability Assay 
     Peptidomimetic macrocycles with optimized linkers possess, for example, ex vivo half-lives that are at least two-fold greater than that of a corresponding uncrosslinked polypeptide, and possess ex vivo half-lives of 12 hours or more. For ex vivo serum stability studies, a variety of assays can be used. For example, a peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide (2 mcg) are incubated with fresh mouse, rat and/or human serum (2 mL) at 37° C. for 0, 1, 2, 4, 8, and 24 hours. To determine the level of intact compound, the following procedure can be used: The samples are extracted by transferring 100 μL of sera to 2 ml centrifuge tubes followed by the addition of 10 μL of 50% formic acid and 500 μL acetonitrile and centrifugation at 14,000 RPM for 10 min at 4±2° C. The supernatants are then transferred to fresh 2 ml tubes and evaporated on Turbovap under N 2 &lt;10 psi, 37° C. The samples are reconstituted in 100 μL of 50:50 acetonitrile:water and submitted to LC-MS/MS analysis. 
     Example 5 
     In vitro Binding Assays 
     To assess the binding and affinity of peptidomimetic macrocycles and peptidomimetic precursors to acceptor proteins, a fluorescence polarization assay (FPA) is used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and a fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation compared to fluorescent tracers attached to smaller molecules (e.g. FITC-labeled peptides that are free in solution). 
     For example, fluoresceinated peptidomimetic macrocycles (25 nM) are incubated with the acceptor protein (25-1000 nM) in binding buffer (140 mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). K d  values can be determined by nonlinear regression analysis using, for example, GraphPad Prism software (GraphPad Software, Inc., San Diego, Calif.). A peptidomimetic macrocycle shows, in some embodiments, similar or lower K d  value than a corresponding uncrosslinked polypeptide. 
     Example 6 
     In Vitro Displacement Assays to Characterize Antagonists of Peptide-Protein Interactions 
     To assess the binding and affinity of compounds that antagonize the interaction between a peptide and an acceptor protein, a fluorescence polarization assay (FPA) utilizing a fluoresceinated peptidomimetic macrocycle derived from a peptidomimetic precursor sequence is used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation as compared to fluorescent tracers attached to smaller molecules (e.g. FITC-labeled peptides that are free in solution). A compound that antagonizes the interaction between the fluoresceinated peptidomimetic macrocycle and an acceptor protein will be detected in a competitive binding FPA experiment. 
     For example, putative antagonist compounds (1 nM to 1 mM) and a fluoresceinated peptidomimetic macrocycle (25 nM) are incubated with the acceptor protein (50 nM) in binding buffer (140 mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Antagonist binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). K d  values can be determined by nonlinear regression analysis using, for example, Graphpad Prism software (GraphPad Software, Inc., San Diego, Calif.). 
     Any class of molecule, such as small organic molecules, peptides, oligonucleotides or proteins can be examined as putative antagonists in this assay. 
     Example 7 
     Assay for Protein-Ligand Binding by Affinity Selection-Mass Spectrometry 
     To assess the binding and affinity of test compounds for proteins, an affinity-selection mass spectrometry assay is used, for example. Protein-ligand binding experiments are conducted according to the following representative procedure outlined for a system-wide control experiment using 1 μM peptidomimetic macrocycle plus 5 μM hMDM2. A 1 μL, DMSO aliquot of a 40 μM stock solution of peptidomimetic macrocycle is dissolved in 19 μL of PBS (Phosphate-buffered saline: 50 mM, pH 7.5 Phosphate buffer containing 150 mM NaCl). The resulting solution is mixed by repeated pipetting and clarified by centrifugation at 10,000 g for 10 min. To a 4 μL aliquot of the resulting supernatant is added 4 μL of 10 μM hMDM2 in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS plus 1 μM peptidomimetic macrocycle and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated for 60 min at room temperature, and then chilled to 4° C. prior to size-exclusion chromatography-LC-MS analysis of 5.0 μL injections. Samples containing a target protein, protein-ligand complexes, and unbound compounds are injected onto an SEC column, where the complexes are separated from non-binding component by a rapid SEC step. The SEC column eluate is monitored using UV detectors to confirm that the early-eluting protein fraction, which elutes in the void volume of the SEC column, is well resolved from unbound components that are retained on the column. After the peak containing the protein and protein-ligand complexes elutes from the primary UV detector, it enters a sample loop where it is excised from the flow stream of the SEC stage and transferred directly to the LC-MS via a valving mechanism. The (M+3H) 3+  ion of the peptidomimetic macrocycle is observed by ESI-MS at the expected m/z, confirming the detection of the protein-ligand complex. 
     Example 8 
     Assay for Protein-Ligand K d  Titration Experiments 
     To assess the binding and affinity of test compounds for proteins, a protein-ligand K d  titration experiment is performed, for example. Protein-ligand K d  titrations experiments are conducted as follows: 2 μL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (5, 2.5, . . . , 0.098 mM) are prepared then dissolved in 38 μL of PBS. The resulting solutions are mixed by repeated pipetting and clarified by centrifugation at 10 000 g for 10 min. To 4.0 μL aliquots of the resulting supernatants is added 4.0 μL of 10 μM hMDM2 in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS, varying concentrations (125, 62.5, . . . , 0.24 μM) of the titrant peptide, and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 30 min, then chilled to 4° C. prior to SEC-LC-MS analysis of 2.0 μL injections. The (M+H) 1+ , (M+2H) 2+ , (M+3H) 3+ , and/or (M+Na) 1+  ion is observed by ESI-MS; extracted ion chromatograms are quantified, then fit to equations to derive the binding affinity K d  as described in Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M.  J. Am. Chem. Soc.  2004, 126, 15495-15503; also in D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in Medicinal Chemistry. Edited by Wanner K, Höfner G: Wiley-VCH; 2007: 121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry. 
     Example 9 
     Assay for Competitive Binding Experiments by Affinity Selection-Mass Spectrometry 
     To determine the ability of test compounds to bind competitively to proteins, an affinity selection mass spectrometry assay is performed, for example. A mixture of ligands at 40 μM per component is prepared by combining 2 μL aliquots of 400 μM stocks of each of the three compounds with 14 μL of DMSO. Then, 1 μL aliquots of this 40 μM per component mixture are combined with 1 μL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (10, 5, 2.5, . . . , 0.078 mM). These 2 μL samples are dissolved in 38 μL of PBS. The resulting solutions were mixed by repeated pipetting and clarified by centrifugation at 10 000 g for 10 min. To 4.0 μL aliquots of the resulting supernatants is added 4.0 μL of 10 μM hMDM2 protein in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS plus 0.5 μM ligand, 2.5% DMSO, and varying concentrations (125, 62.5, . . . , 0.98 μM) of the titrant peptidomimetic macrocycle. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 60 min, then chilled to 4° C. prior to SEC-LC-MS analysis of 2.0 μL injections. Additional details on these and other methods are provided in “ A General Technique to Rank Protein - Ligand Binding Affinities and Determine Allosteric vs. Direct Binding Site Competition in Compound Mixtures.”  Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M.  J. Am. Chem. Soc.  2004, 126, 15495-15503; also in “ ALIS: An Affinity Selection - Mass Spectrometry System for the Discovery and Characterization of Protein - Ligand Interactions”  D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in Medicinal Chemistry. Edited by Wanner K, Höfner G: Wiley-VCH; 2007: 121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry. 
     Example 10 
     Binding Assays in Intact Cells 
     It is possible to measure binding of peptides or peptidomimetic macrocycles to their natural acceptors in intact cells by immunoprecipitation experiments. For example, intact cells are incubated with fluoresceinated (FITC-labeled) compounds for 4 hrs in the absence of serum, followed by serum replacement and further incubation that ranges from 4-18 hrs. Cells are then pelleted and incubated in lysis buffer (50 mM Tris [pH 7.6], 150 mM NaCl, 1% CHAPS and protease inhibitor cocktail) for 10 minutes at 4° C. Extracts are centrifuged at 14,000 rpm for 15 minutes and supernatants collected and incubated with 10 μL goat anti-FITC antibody for 2 hrs, rotating at 4° C. followed by further 2 hrs incubation at 4° C. with protein A/G Sepharose (50 μL of 50% bead slurry). After quick centrifugation, the pellets are washed in lysis buffer containing increasing salt concentration (e.g., 150, 300, 500 mM). The beads are then re-equilibrated at 150 mM NaCl before addition of SDS-containing sample buffer and boiling. After centrifugation, the supernatants are optionally electrophoresed using 4%-12% gradient Bis-Tris gels followed by transfer into Immobilon-P membranes. After blocking, blots are optionally incubated with an antibody that detects FITC and also with one or more antibodies that detect proteins that bind to the peptidomimetic macrocycle. 
     Example 11 
     Cellular Penetrability Assays 
     A peptidomimetic macrocycle is, for example, more cell penetrable compared to a corresponding uncrosslinked macrocycle. Peptidomimetic macrocycles with optimized linkers possess, for example, cell penetrability that is at least two-fold greater than a corresponding uncrosslinked macrocycle, and often 20% or more of the applied peptidomimetic macrocycle will be observed to have penetrated the cell after 4 hours. To measure the cell penetrability of peptidomimetic macrocycles and corresponding uncrosslinked macrocycle, intact cells are incubated with fluorescently-labeled (e.g. fluoresceinated) peptidomimetic macrocycles or corresponding uncrosslinked macrocycle (10 μM) for 4 hrs in serum free media at 37° C., washed twice with media and incubated with trypsin (0.25%) for 10 min at 37° C. The cells are washed again and resuspended in PBS. Cellular fluorescence is analyzed, for example, by using either a FACSCalibur flow cytometer or Cellomics&#39; KineticScan ® HCS Reader. 
     Example 12 
     In Vivo Stability Assay 
     To investigate the in vivo stability of the peptidomimetic macrocycles, the compounds are, for example, administered to mice and/or rats by IV, IP, PO or inhalation routes at concentrations ranging from 0.1 to 50 mg/kg and blood specimens withdrawn at 0′, 5′, 15′, 30′, 1 hr, 4 hrs, 8 hrs and 24 hours post-injection. Levels of intact compound in 25 μL of fresh serum are then measured by LC-MS/MS as above. 
     Example 13 
     Clinical Trials 
     To determine the suitability of the peptidomimetic macrocycles for treatment of humans, clinical trials are performed. For example, patients diagnosed with an infectious disease and in need of treatment can be selected and separated in treatment and one or more control groups, wherein the treatment group is administered a peptidomimetic macrocycle, while the control groups receive a placebo or a known antimicrobial drug. The treatment safety and efficacy of the peptidomimetic macrocycles can thus be evaluated by performing comparisons of the patient groups with respect to factors such as survival and quality-of-life. In this example, the patient group treated with a peptidomimetic macrocycle can show improved long-term survival compared to a patient control group treated with a placebo. 
     Example 14 
     Synthesis of Hydrocarbon-Containing Peptidomimetic Macrocycle with β-Hairpin Secondary Structure 
     The hydrocarbon-containing peptidomimetic macrocycles of the inventions with β-hairpin secondary structures were prepared by assembling a linear sequence of peptides with an N-terminal 5-aminovaleric acid group on a chlorotrityl chloride resin. The fully-protected linear peptide was then cleaved from the resin to afford an intermediate with a free C-terminal carboxyl group and an N-terminal amino group. Cyclization of the intermediate peptide in solution was initiated using the diphenyl phosphorazidate (DPPA) method to afford a lactam bridge. TFA deprotection of all the protecting groups, followed by HPLC purification and a salt exchange generated the desired peptidomimetic macrocycle, as shown in SCHEME 1. 
     
       
         
         
             
             
         
       
     
     Example 15 
     Synthesis of Triazole-Containing Peptidomimetic Macrocycle with β-Hairpin Secondary Structure 
     The triazole-containing peptidomimetic macrocycles with β-hairpin secondary structures were prepared by assembling a linear sequence of peptides with an N-terminal azidoacetyl group on a chlorotrityl chloride resin. The fully-protected linear peptide was then cleaved from the resin to afford an intermediate with a free C-terminal carboxyl group and an N-terminal amino group. Cyclization of the propargyl amine to the C-terminal carboxyl group was initiated in solution using the diphenyl phosphorazidate (DPPA) method. Cyclization of the resulting intermediate peptide was conducted through a Click reaction in solution to form a triazole linker. TFA deprotection of all the protecting groups, followed by HPLC purification and a salt exchange generated the desired peptidomimetic macrocycle, as shown in SCHEME 2. 
     
       
         
         
             
             
         
       
     
     Pharmaceutical Compositions and Routes of Administration 
     In some embodiments, peptidomimetic macrocycles are modified by covalently or non-covalently joining appropriate functional groups to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion. 
     Pharmaceutically-acceptable salts of the compounds disclosed herein include those derived from pharmaceutically-acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl) 4   +  salts. 
     For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically-acceptable carriers include either solid or liquid carriers. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which also acts as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington&#39;s Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. 
     In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. 
     Suitable solid excipients are carbohydrate or protein fillers include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents are added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. 
     Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. 
     The pharmaceutical preparation can be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. 
     When one or more compositions disclosed herein comprise a combination of a peptidomimetic macrocycle and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. In some embodiments, the additional agents are administered separately, as part of a multiple dose regimen, from one or more compounds disclosed herein. Alternatively, those agents are part of a single dosage form, mixed together with the compounds disclosed herein in a single composition. 
     Methods of Use 
     Combination Treatment 
     In some embodiments, combination therapy can be advantageous, since the therapeutic (for e.g. antimicrobial) efficacy of a drug could be enhanced compared to the use of each compound alone. The dosage of each agent in a combination therapy may also be reduced compared to monotherapy using each agent, while still achieving an overall therapeutic (e.g. antimicrobial) efficacy. In some embodiments, the peptidomimetic macrocycles of the disclosure can exhibit synergistic effects when administered with additional pharmaceutical agents. In such cases, the total amount of drugs administered to a patient could be reduced, which could reduce side effects. 
     The present disclosure also provides methods for administering combination therapies in which the peptidomimetic macrocycles of the disclosure are used in combination with at least one additional pharmaceutically-active agent. In some embodiments, at least one additional pharmaceutically-active agent may be capable of modulating the same or a different target as the peptidomimetic macrocycles of the disclosure. In some embodiments, at least one additional pharmaceutically-active agent may modulate the same target as the peptidomimetic macrocycles of the disclosure, other components of the same pathway, or overlapping sets of target enzymes. In some embodiments, at least one additional pharmaceutically-active agent may modulate a different target as the peptidomimetic macrocycles of the disclosure. 
     In one embodiment, the present disclosure provides a method for treating a disorder (e.g., infectious disease), the method comprising administering to a subject in need thereof (a) an effective amount of a peptidomimetic macrocycle of the disclosure and (b) an effective amount of at least one additional pharmaceutically-active agent to provide a combination therapy. In some embodiments, combination therapy may have an enhanced therapeutic effect compared to the effect of administering the peptidomimetic macrocycle or the pharmaceutically-active agent alone. According to certain exemplary embodiments, combination therapy can have a synergistic therapeutic effect and can produce significantly better therapeutic results (e.g., antimicrobial) than the additive effects achieved by each individual constituent when administered alone at therapeutic doses. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with one or more antimicrobial drug. Suitable antimicrobial drugs for use in combination therapy of the present disclosure include, but are not limited to, aminoglycosides, carbapenems and other penems, cephalosporins, cyclic esters, fluoro- and other quinolones, glycopeptides, glycylcyclines, lipopeptides, macrolides and ketolides, monobactams, oxazolidinones, penicillins, polymyxins, rifamycins, amdinopenicillins, amphenicols, cephalosporins, lincosamides, antistaphylococcal penicillins, pleuromutilins, pseudomonic acids, riminofenazines, steroid antibacterials, streptogramins, sulfonamides/dihydrofolate reductase inhibitors and combinations, sulfones, tetracyclines, aminocyclitols, cyclic polypeptides, nitrofurantoins, nitroimidazoles, and any combination thereof. 
     In some examples, the peptidomimetic macrocycles of the disclosure are used in combination with one or more antimetabolites, for example in combination with capecitabine (XELODA), gemcitabine (GEMZAR) and cytarabine (cytosine arabinoside, also known as ara-C (arabinofuranosyl cytidine; Cytosar-U)). 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with taxanes. Exemplary non-limiting taxanes that may be used in combination with the instant peptidomimetic macrocycles include paclitaxel (ABRAXANE or TAXOL) and docetaxel (TAXOTERE). In some embodiments the peptidomimetic macrocycles of the instant disclosure are used in combination with paclitaxel. In some embodiments the peptidomimetic macrocycles of the instant disclosure are used in combination with docetaxel. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with aminoglycosides. Examples of aminoglycosides that can be combined with compounds of this disclosure include but are not limited to amikacin, arbekacin, bekanamycin, dibekacin, dihydrostreptomycin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, ribostamycin, sisomicin, streptoduocin, streptomycin, and tobramycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with carbapenems or other penems. Examples of carbapenems or other penems that can be combined with compounds of this disclosure include but are not limited to biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, and panipenem. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with cephalosporins. Examples of cephalosporins that can be combined with compounds of this disclosure include but are not limited to cefcapene, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefoperazone, cefoselis, cefotaxime, cefozopran, cefpiramide, cefpirome, cefpodoxime, cefsulodin, ceftaroline, ceftazidime, ceftizoxime, ceftobiprole, ceftibuten, ceftriaxone, and latamoxef. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with cyclic esters. Examples of cyclic esters that can be combined with compounds of this disclosure include but are not limited to fosfomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with fluoro- or other quinolones. Examples of fluoro- or other quinolones that can be combined with compounds of this disclosure include but are not limited to cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, prulifloxacin, rosoxacin, rufloxacin, sitafloxacin, sparfloxacin, temafloxacin, and trovafloxacin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with glycopeptides. Examples of glycopeptides that can be combined with compounds of this disclosure include but are not limited to dalbavancin, oritavancin, teicoplanin, telavancin, and vancomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with glycylcyclines. Examples of glycylcyclines that can be combined with compounds of this disclosure include but are not limited to tigecycline. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with lipopeptides. Examples of lipopeptides that can be combined with compounds of this disclosure include but are not limited to daptomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with macrolides. Examples of macrolides that can be combined with compounds of this disclosure include but are not limited to azithromycin, clarithromycin, erythromycin, dirithromycin, flurithromycin, josamycin, midecamycin, miocamycin, oleandomycin, rokitamycin, roxithromycin, spiramycin, telithromycin, and troleandomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with monobactams. Examples of monobactams that can be combined with compounds of this disclosure include but are not limited to aztreonam and carumonam. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with oxazolidinones. Examples of oxazolidinones that can be combined with compounds of this disclosure include but are not limited to linezolid. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with Penicillins. Examples of Penicillins that can be combined with compounds of this disclosure include but are not limited to amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, carbenicillin, carindacillin, clometocillin, epicillin, hetacillin, metampicillin, methicillin, mezlocillin, penamecillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), pheneticillin, piperacillin, pivampicillin, propicillin, sulbenicillin, sultamicillin, talampicillin, temocillin, and ticarcillin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with polymyxins. Examples of polymyxins that can be combined with compounds of this disclosure include but are not limited to colistin and polymyxin B. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with rifamycins. Examples of rifamycins that can be combined with compounds of this disclosure include but are not limited to rifabutin, rifampicin (rifampin), rifaximin, rifapentine, and rifamycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with amdinopenicillins. Examples of amdinopenicillins that can be combined with compounds of this disclosure include but are not limited to mecillinam and pivmecillinam. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with amphenicols. Examples of amphenicols that can be combined with compounds of this disclosure include but are not limited to chloramphenicol and thiamphenicol. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with cephalosporins. Examples of cephalosporins that can be combined with compounds of this disclosure include but are not limited to cefaclor, cefacetrile, cefadroxil, cefaloridine, cephalexin, cefalotin, cefamandole, cefapirin, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefmetazole, cefminox, cefonicid, ceforanide, cefotetan, cefotiam, cefoxitin, cefprozil, cefradine, cefroxadine, ceftezole, cefuroxime, flomoxef, and loracarbef. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with lincosamides. Examples of lincosamides that can be combined with compounds of this disclosure include but are not limited to clindamycin and lincomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with antistaphylococcal penicillins. Examples of antistaphylococcal penicillins that can be combined with compounds of this disclosure include but are not limited to cloxacilllin, dicloxacillin, flucloxacillin, oxacillin, and nafcillin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with pleuromutilins. Examples of pleuromutilins that can be combined with compounds of this disclosure include but are not limited to retapamulin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with pseudomonic acids. Examples of pseudomonic acids that can be combined with compounds of this disclosure include but are not limited to mupirocin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with riminofenazines. Examples of riminofenazines that can be combined with compounds of this disclosure include but are not limited to clofazimine. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with steroid antibacterials. Examples of steroid antibacterials that can be combined with compounds of this disclosure include but are not limited to fusidic acid. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with streptogramins. Examples of streptogramins that can be combined with compounds of this disclosure include but are not limited to quinupristin/dalfopristin pristinamycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with sulfonamides/dihydrofolate reductase inhibitors. Examples of sulfonamides/dihydrofolate reductase inhibitors that can be combined with compounds of this disclosure include but are not limited to brodimoprim, iclaprim, pyrimethamine, sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, (sulfisoxazole), sulfaisodimidine, sulfalene, sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine, sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfapyridine, sulfathiazole, sulfathiourea, tetroxoprim, and trimethoprim. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with sulfones. Examples of sulfones that can be combined with compounds of this disclosure include but are not limited to dapsone and aldesulfone. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with tetracyclines. Examples of tetracyclines that can be combined with compounds of this disclosure include but are not limited to chlortetracycline, clomocycline, demeclocycline, doxycycline, lymecycline, metacycline, minocycline, penimepicycline, rolitetracycline, oxytetracycline, and tetracycline. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with aminocyclitols. Examples of aminocyclitols that can be combined with compounds of this disclosure include but are not limited to spectinomycin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with cyclic polypeptides. Examples of cyclic polypeptides that can be combined with compounds of this disclosure include but are not limited to bacitracin. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with nitrofurantoins. Examples of nitrofurantoins that can be combined with compounds of this disclosure include but are not limited to furazolidone, nitrofurantoin, nifurtoinol, and nitrofural. 
     In some embodiments, the peptidomimetic macrocycles of the disclosure are used in combination with nitroimidazoles. Examples of nitroimidazoles that can be combined with compounds of this disclosure include but are not limited to metronidazole, tinidazole, and ornidazole. 
     The table below lists various suitable additional pharmaceutically-active agents for use with the methods described herein. 
     
       
         
           
               
               
             
               
                   
               
               
                 Generic name 
                 Brand names 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Aminoglycosides 
               
            
           
           
               
               
            
               
                 Amikacin 
                 Amikin ™ 
               
               
                 Gentamicin 
                 Garamycin ™ 
               
               
                 Kanamycin 
                 Kantrex ™ 
               
               
                 Neomycin 
                 Neo-Fradin ™ 
               
               
                 Netilmicin 
                 Netromycin ™ 
               
               
                 Tobramycin 
                 Nebcin ™ 
               
               
                 Paromomycin 
                 Humatin ™ 
               
               
                 Streptomycin 
               
               
                 Spectinomycin (Bs) 
                 Trobicin ™ 
               
            
           
           
               
            
               
                 Ansamycins 
               
            
           
           
               
               
            
               
                 Geldanamycin 
                   
               
               
                 Herbimycin 
               
               
                 Rifaximin 
                 Xifaxan ™ 
               
            
           
           
               
            
               
                 Carbacephem 
               
            
           
           
               
               
            
               
                 Loracarbef 
                 Lorabid ™ 
               
            
           
           
               
            
               
                 Carbapenems 
               
            
           
           
               
               
            
               
                 Ertapenem 
                 Invanz ™ 
               
               
                 Doripenem 
                 Doribax ™ 
               
               
                 Imipenem/Cilastatin 
                 Primaxin ™ 
               
               
                 Meropenem 
                 Merrem ™ 
               
            
           
           
               
            
               
                 Cephalosporins (First generation) 
               
            
           
           
               
               
            
               
                 Cefadroxil 
                 Duricef ™ 
               
               
                 Cefazolin 
                 Ancef ™ 
               
               
                 Cefalotin or Cefalothin 
                 Keflin ™ 
               
               
                 Cefalexin 
                 Keflex ™ 
               
            
           
           
               
            
               
                 Cephalosporins (Second generation) 
               
            
           
           
               
               
            
               
                 Cefaclor 
                 Distaclor ™ 
               
               
                 Cefamandole 
                 Mandol ™ 
               
               
                 Cefoxitin 
                 Mefoxin ™ 
               
               
                 Cefprozil 
                 Cefzil ™ 
               
               
                 Cefuroxime 
                 Ceftin TM, Zinnat ™ 
               
            
           
           
               
            
               
                 Cephalosporins (Third generation) 
               
            
           
           
               
               
            
               
                 Cefixime 
                 Cefspan ™ 
               
               
                 Cefdinir 
                 Omnicef TM, Cefdiel ™ 
               
               
                 Cefditoren 
                 Spectracef TM, Meiact ™ 
               
               
                 Cefoperazone 
                 Cefobid ™ 
               
               
                 Cefotaxime 
                 Claforan ™ 
               
               
                 Cefpodoxime 
                 Vantin ™ 
               
               
                 Ceftazidime 
                 Fortaz ™ 
               
               
                 Ceftibuten 
                 Cedax ™ 
               
               
                 Ceftizoxime 
                 Cefizox ™ 
               
               
                 Ceftriaxone 
                 Rocephin ™ 
               
            
           
           
               
            
               
                 Cephalosporins (Fourth generation) 
               
            
           
           
               
               
            
               
                 Cefepime 
                 Maxipime ™ 
               
            
           
           
               
            
               
                 Cephalosporins (Fifth generation) 
               
            
           
           
               
               
            
               
                 Ceftaroline fosamil 
                 Teflaro ™ 
               
               
                 Ceftobiprole 
                 Zeftera ™ 
               
            
           
           
               
            
               
                 Glycopeptides 
               
            
           
           
               
               
            
               
                 Teicoplanin 
                 Targocid ™ 
               
               
                 Vancomycin 
                 Vancocin ™ 
               
               
                 Telavancin 
                 Vibativ ™ 
               
               
                 Dalbavancin 
                 Dalvance ™ 
               
               
                 Oritavancin 
                 Orbactiv ™ 
               
            
           
           
               
            
               
                 Lincosamides (Bs) 
               
            
           
           
               
               
            
               
                 Clindamycin 
                 Cleocin ™ 
               
               
                 Lincomycin 
                 Lincocin ™ 
               
            
           
           
               
            
               
                 Lipopeptide 
               
            
           
           
               
               
            
               
                 Daptomycin 
                 Cubicin ™ 
               
            
           
           
               
            
               
                 Macrolides (Bs) 
               
            
           
           
               
               
            
               
                 Azithromycin 
                 Zithromax ™, Sumamed ™, 
               
               
                   
                 Xithrone ™ 
               
               
                 Clarithromycin 
                 Biaxin ™ 
               
               
                 Dirithromycin 
                 Dynabac ™ 
               
               
                 Erythromycin 
                 Erythocin ™, Erythroped ™ 
               
               
                 Roxithromycin 
               
               
                 Troleandomycin 
                 Tao ™ 
               
               
                 Telithromycin 
                 Ketek ™ 
               
               
                 Spiramycin 
                 Rovamycine ™ 
               
            
           
           
               
            
               
                 Monobactams 
               
            
           
           
               
               
            
               
                 Aztreonam 
                 Azactam ™ 
               
            
           
           
               
            
               
                 Nitrofurans 
               
            
           
           
               
               
            
               
                 Furazolidone 
                 Furoxone ™ 
               
               
                 Nitrofurantoin (Bs) 
                 Macrodantin ™, Macrobid ™ 
               
            
           
           
               
            
               
                 Oxazolidinones (Bs) 
               
            
           
           
               
               
            
               
                 Linezolid 
                 Zyvox ™ 
               
               
                 Posizolid 
               
               
                 Radezolid 
               
               
                 Torezolid 
               
            
           
           
               
            
               
                 Penicillins 
               
            
           
           
               
               
            
               
                 Amoxicillin 
                 Novamox ™, Amoxil ™ 
               
               
                 Ampicillin 
                 Principen ™ 
               
               
                 Azlocillin 
               
               
                 Carbenicillin 
                 Geocillin ™ 
               
               
                 Cloxacillin 
                 Tegopen ™ 
               
               
                 Dicloxacillin 
                 Dynapen ™ 
               
               
                 Flucloxacillin 
                 Floxapen ™ 
               
               
                 Mezlocillin 
                 Mezlin ™ 
               
               
                 Methicillin 
                 Staphcillin ™ 
               
               
                 Nafcillin 
                 Unipen ™ 
               
               
                 Oxacillin 
                 Prostaphlin ™ 
               
               
                 Penicillin G 
                 Pentids ™ 
               
               
                 Penicillin V 
                 Veetids ™ 
               
               
                 Piperacillin 
                 Pipracil ™ 
               
               
                 Penicillin G 
                 Pfizerpen ™ 
               
               
                 Temocillin 
                 Negaban ™ 
               
               
                 Ticarcillin 
                 Ticar ™ 
               
            
           
           
               
            
               
                 Penicillin combinations 
               
            
           
           
               
               
            
               
                 Amoxicillin/clavulanate 
                 Augmentin ™ 
               
               
                 Ampicillin/sulbactam 
                 Unasyn ™ 
               
               
                 Piperacillin/tazobactam 
                 Zosyn ™ 
               
               
                 Ticarcillin/clavulanate 
                 Timentin ™ 
               
            
           
           
               
            
               
                 Polypeptides 
               
            
           
           
               
               
            
               
                 Bacitracin 
                   
               
               
                 Colistin 
                 Coly-Mycin-S ™ 
               
               
                 Polymyxin B 
               
            
           
           
               
            
               
                 Quinolones/Fluoroquinolone 
               
            
           
           
               
               
            
               
                 Ciprofloxacin 
                 Cipro ™, Ciproxm ™, Ciprobay ™ 
               
               
                 Enoxacin 
                 Penetrex ™ 
               
               
                 Gatifloxacin 
                 Tequin ™ 
               
               
                 Gemifloxacin 
                 Factive ™ 
               
               
                 Levofloxacin 
                 Levaquin ™ 
               
               
                 Lomefloxacin 
                 Maxaquin ™ 
               
               
                 Moxifloxacin 
                 Avelox ™ 
               
               
                 Nalidixic acid 
                 NegGram ™ 
               
               
                 Norfloxacin 
                 Noroxin ™ 
               
               
                 Ofloxacin 
                 Floxin ™, Ocuflox ™ 
               
               
                 Trovafloxacin 
                 Trovan ™ 
               
               
                 Grepafloxacin 
                 Raxar ™ 
               
               
                 Sparfloxacin 
                 Zagam ™ 
               
               
                 Temafloxacin 
                 Omniflox ™ 
               
            
           
           
               
            
               
                 Sulfonamides (Bs) 
               
            
           
           
               
               
            
               
                 Mafenide 
                 Sulfamylon ™ 
               
               
                 Sulfacetamide 
                 Sulamyd ™, Bleph-10 ™ 
               
               
                 Sulfadiazine 
                 Micro-Sulfon ™ 
               
               
                 Silver sulfadiazine 
                 Silvadene ™ 
               
               
                 Sulfadimethoxine 
                 Di-Methox TM, Albon ™ 
               
               
                 Sulfamethizole 
                 Thiosulfil Forte ™ 
               
               
                 Sulfamethoxazole 
                 Gantanol ™ 
               
               
                 Sulfanilimide (archaic) 
               
               
                 Sulfasalazine 
                 Azulfidine ™ 
               
               
                 Sulfisoxazole 
                 Gantrisin ™ 
               
               
                 Trimethoprim- 
                 Bactrim ™, Septra ™ 
               
               
                 Sulfamethoxazole (Co- 
               
               
                 trimoxazole) (TMP-SMX) 
               
               
                 Sulfonamidochrysoidine (archaic) 
                 Prontosil ™ 
               
            
           
           
               
            
               
                 Tetracyclines (Bs) 
               
            
           
           
               
               
            
               
                 Demeclocycline 
                 Declomycin ™ 
               
               
                 Doxycycline 
                 Vibramycin ™ 
               
               
                 Minocycline 
                 Minocin ™ 
               
               
                 Oxytetracycline 
                 Terramycin ™ 
               
               
                 Tetracycline 
                 Sumycin ™, Achromycin V ™, 
               
               
                   
                 Steclin ™ 
               
            
           
           
               
            
               
                 Drugs against mycobacteria 
               
            
           
           
               
               
            
               
                 Clofazimine 
                 Lamprene ™ 
               
               
                 Dapsone 
                 Avlosulfon ™ 
               
               
                 Capreomycin 
                 Capastat ™ 
               
               
                 Cycloserine 
                 Seromycin ™ 
               
               
                 Ethambutol (Bs) 
                 Myambutol ™ 
               
               
                 Ethionamide 
                 Trecator ™ 
               
               
                 Isoniazid 
                 I.N.H. ™ 
               
               
                 Pyrazinamide 
                 Aldinamide ™ 
               
               
                 Rifampicin (Rifampin in US) 
                 Rifadin ™, Rimactane ™ 
               
               
                 Rifabutin 
                 Mycobutin ™ 
               
               
                 Rifapentine 
                 Priftin ™ 
               
               
                 Streptomycin 
               
            
           
           
               
            
               
                 Others 
               
            
           
           
               
               
            
               
                 Arsphenamine 
                 Salvarsan ™ 
               
               
                 Chloramphenicol (Bs) 
                 Chloromycetin ™ 
               
               
                 Fosfomycin 
                 Monurol ™, Monuril ™ 
               
               
                 Fusidic acid 
                 Fucidin ™ 
               
               
                 Metronidazole 
                 Flagyl ™ 
               
               
                 Mupirocin 
                 Bactroban ™ 
               
               
                 Platensimycin 
               
               
                 Quinupristin/Dalfopristin 
                 Synercid ™ 
               
               
                 Thiamphenicol 
               
               
                 Tigecycline (Bs) 
                 Tigacyl ™ 
               
               
                 Tinidazole 
                 Tindamax Fasigyn ™ 
               
               
                 Trimethoprim (Bs) 
                 Proloprim ™, Trimpex ™ 
               
               
                   
               
            
           
         
       
     
     The peptidomimetic macrocycles and an additional pharmaceutically-active agent can be administered simultaneously or sequentially. 
     Simultaneous administration of two or more compounds can occur either via the same pharmaceutical composition or via separate pharmaceutical compositions. Simultaneous administration of two compounds can occur when the two compounds are administered to the same subject within a time frame that is, for example, no more than about 0 minutes, no more than about 1 minute, no more than about 2 minutes, no more than about 3 minutes, no more than about 4 minutes, no more than about 5 minutes, no more than about 6 minutes, no more than about 7 minutes, no more than about 8 minutes, no more than about 9 minutes, no more than about 10 minutes, no more than about 11 minutes, no more than about 12 minutes, no more than about 13 minutes, no more than about 14 minutes, or no more than about 15 minutes. Sequential administration can occur when the two compounds are administered to the same subject after a time frame that is, for example, at least about 15 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, or at least about 60 minutes. The compounds can be administered in any order. 
     In some embodiments, the administration of the peptidomimetic macrocycles and the additional pharmaceutically-active agent are concurrent, i.e., the administration period of the peptidomimetic macrocycles and that of the agent overlap with each other. In some embodiments, the administration of the peptidomimetic macrocycles and the additional pharmaceutically-active agent are non-concurrent. For example, in some embodiments, the administration of the peptidomimetic macrocycles is terminated before the additional pharmaceutically-active agent is administered. In some embodiments, the administration of the additional pharmaceutically-active agent is terminated before the peptidomimetic macrocycle is administered. The time period between these two non-concurrent administrations can range from being days apart to being weeks apart. 
     The dosing frequency of the peptidomimetic macrocycle and at least one additional pharmaceutically-active agent may be adjusted over the course of the treatment, based on the judgment of the administering physician. When administered separately, the peptidomimetic macrocycle and additional pharmaceutically-active agent(s) can be administered at different dosing frequency or intervals. For example, the peptidomimetic macrocycle can be administered weekly, while the additional pharmaceutically-active agent(s) can be administered more or less frequently. Or, the peptidomimetic macrocycle can be administered twice weekly, while the additional pharmaceutically-active agent(s) can be administered more or less frequently. In addition, the peptidomimetic macrocycle and the additional pharmaceutically-active agent(s) can be administered using the same route of administration or using different routes of administration. 
     According to certain embodiments, the peptidomimetic macrocycles and the additional pharmaceutically-active agent are administered within a single pharmaceutical composition. According to some embodiments, the pharmaceutical composition further comprises pharmaceutically-acceptable diluents or carriers. According to certain embodiments, the peptidomimetic macrocycles and the additional pharmaceutically-active agent(s) are administered within different pharmaceutical compositions. 
     According to certain embodiments, the peptidomimetic macrocycle is administered in an amount of from 0 mg/kg body weight to 100 mg/kg body weight. According to other embodiments, the peptidomimetic macrocycle is administered at an amount of from about 0.5 mg/kg body weight to abpit 20 mg/kg body weight. According to additional embodiments, the peptidomimetic macrocycle is administered at an amount of from about 1.0 mg/kg body weight to about 10 mg/kg body weight. At least one additional pharmaceutical agent is administered at the therapeutic amount known to be used for treating the specific type of the disease. According to other embodiments, at least one additional pharmaceutical agent is administered in an amount lower than the therapeutic amount known to be used for treating the disease, i.e. a sub-therapeutic amount of at least one additional pharmaceutical agent is administered.